CN112262129A - Triazacyclododecane sulfonamide ("TCD") based protein secretion inhibitors - Google Patents
Triazacyclododecane sulfonamide ("TCD") based protein secretion inhibitors Download PDFInfo
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- CN112262129A CN112262129A CN201980032763.5A CN201980032763A CN112262129A CN 112262129 A CN112262129 A CN 112262129A CN 201980032763 A CN201980032763 A CN 201980032763A CN 112262129 A CN112262129 A CN 112262129A
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Provided herein are triazacyclododecanesulfonamide ("TCD") based protein secretion inhibitors (e.g., Sec61 inhibitors), methods of making the same, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of formula (I) and pharmaceutically acceptable salts, and compositions comprising the same. The compounds disclosed herein are useful in the examplesSuch as treating diseases including inflammation and/or cancer.
Description
Technical Field
The present disclosure relates to triazacyclododecanesulfonamide ("TCD") based protein secretion inhibitors, including methods of making and using the same.
Electronic filing material incorporated by reference
This application contains as a separate part of the disclosure a sequence listing in computer readable form (filename: 40056P2_ seqliking. txt; 20,193 bytes; established on 2019, 2 month 11), which is incorporated herein by reference in its entirety.
Background
The transfer of proteins to the endoplasmic reticulum ("ER") constitutes the first step in protein secretion. In all eukaryotic cells, ER protein import is essential and is particularly important for rapidly growing tumor cells. Thus, the process of protein secretion can serve as a target for potential cancer drugs and bacterial virulence factors. See Kalies andTraffic,16(10):1027-1038(2015)。
when the N-terminal hydrophobic signal peptide protrudes from the ribosome, protein transport to the ER in the cytoplasm begins. When the signal recognition particle ("SRP") binds to the signal sequence, it targets the ribosome-nascent strand-SRP complex to the ER membrane and drives the transfer of the signal peptide to Sec61 upon contact of the SRP with its receptor. Sec61 is a doughnut-shaped ER membrane transporter (aka translocon) composed of 3 major subunits (heterotrimers). It contains a "plug" that blocks protein entry and exit into the ER. When the hydrophobic region of the nascent polypeptide interacts with the "junction" region of Sec61, the plug is displaced allowing the polypeptide to migrate into the ER lumen. In mammals, only short proteins (less than 160 amino acids) can enter the ER post-translationally, while proteins of less than 120 amino acids enforce this pathway. Some trafficking ability is via calmodulin binding to a signal sequence. Upon reaching the Sec61 channel, a signal peptide or signal anchor is inserted between transmembrane regions ("TMD") 2 and 7 of Sec61 α, forming a lateral portion of the gateway that opens the channel for soluble secreted proteins to pass through. When the Sec61 channel is composed of 10 TMDs (Sec61 α) surrounded by hydrophobic clamps formed by Sec61 γ, the channel opening depends on the structural changes that all TMDs actually participate in.
Inhibition of protein transport through the ER membrane has the potential to treat or prevent diseases such as cancer cell growth and inflammatory responses. Known secretion inhibitors range from broad-spectrum to highly substrate-specific, interfering with almost any stage of the multistep process, and even interfering with the transport of endocytosed antigen into the cytoplasm for cross-presentation. These inhibitors block receptor binding or prevent structural changes required for protein trafficking into the ER via interaction with signal peptides, chaperones or the Sec61 channel. Examples of protein secretion inhibitors include calmodulin inhibitors (e.g., E6 Berbamine and Ophiobolin a), lanthanum, sterols, cyclic esterpeptides (e.g., HUN-7293, CAM741, NFI028, cotrinsin, apraxin a, Decatransin, valinomycin), CADA, intra-lipoxin (mycolactione), eyareurestatin I ("ESI"), and exotoxin a. However, these above secretion inhibitors suffer from one or more of the following: the lack of Sec61 channel selectivity, manufacturing challenges due to structural complexity, molecular weight limitations for drug delivery, bioavailability and distribution.
Therefore, there is a need for new small molecule protein secretion inhibitors.
Disclosure of Invention
In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein: raAnd RbEach independently is H or C1-3An alkyl group; r1Is H, OH, C1-3Alkyl, OC1-3Alkyl, ═ CH2Or as NOR5(ii) a Or R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl and forms a spiro ring group with the ring carbon to which it is attached; r1aAnd R1bEach independently is H or C1-3An alkyl group; r2Is C1-6Alkyl, N (R)5)2、C3-8Cycloalkyl radical, C3-9Heterocycloalkyl radical, C3-9Heterocycloalkenyl or C6-10An aryl group; r3Is H, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group; r4Is C3-8Cycloalkyl radical, C3-9Heterocycloalkyl radical, C6-10Aryl or C2-9A heteroaryl group; each R5Independently H, C1-3Alkyl or C0-2alkylene-C6-10An aryl group; x is absent, C1-3Alkylene, C ═ O, or (C ═ O) O; y is SO or SO2(ii) a Each heterocycloalkyl, heterocycloalkenyl, and heteroaryl independently has 1,2, or 3 ring heteroatoms selected from N, O and S.
In some embodiments, each Y is SO. In various embodiments, each Y is SO2。
In different cases, RaIs H. In some cases, RaIs C1-3An alkyl group. In some embodiments, RaIs CH3. In some embodiments, RbIs H. In various embodiments, RbIs C1-3An alkyl group. In different cases, RbIs CH3. In each case RaAnd RbIs H.
In some cases, R1Is H, OH or NOR5. In each case R5Independently H, C1-3Alkyl or C0-2alkylene-C6-10And (4) an aryl group. In some cases, R5Is H or CH3. In some embodiments, R1Is C1-3Alkyl or OC1-3An alkyl group. In various embodiments, R1Is CH3Or OCH3. In some cases, R1Is CH3And exhibits S stereochemistry. In different entitiesIn the embodiment, R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl, and forms a spiro ring group with the ring carbon to which it is attached. In some cases, R1Together with the ring atoms to which they are attachedIn different cases, R1Is ═ CH2。
In some cases, R1aAnd R1bEach is H. In some cases, R1aAnd R1bAt least one of them is C1-3An alkyl group. In some cases, R1aAnd R1bEach is CH3。
In some embodiments, R2Is C1-6Alkyl or N (R)5)2. In each case R5Independently comprise H, C1-3Alkyl or benzyl. In various embodiments, R2Is Et, iPr, N (CH)3)2、In some cases, R2Comprising C3-8A cycloalkyl group. In different cases, R2Including cyclopentyl or cyclohexyl. In some embodiments, R2Is C3-9Heterocycloalkyl or C3-9A heterocycloalkenyl group. In various embodiments, R2Including oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, or tetrahydropyridinyl. In various embodiments, C3-9Heterocycloalkyl or C3-9Heterocycloalkenyl groups comprise a bridging group or a spiro group. In some cases, C comprising a bridging or spiro group3-9The heterocycloalkyl group being selected fromAndand R is6Is C1-6Alkyl radical, C3-8Cycloalkyl or C6-10And (4) an aryl group. In some cases, R6Is optionally substituted by 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy and phenyl substituted by the group of CN. In different cases, R2Selected from the group consisting of:
in some cases, R2Selected from the group consisting of: in different cases, R2Is C6-10And (4) an aryl group. In some embodiments, R2Is composed of
In various embodiments, X is absent. In some embodiments, R3Comprising C1-6Alkyl or H. In some cases, R3Is 2-methylbutyl, isopropyl, isoamyl, CH2CH2OCH3、CH2C(CH3)2CN、CH2CF3Or CH2CH2CF3. In different cases, R3Is an isobutyl group.
In some embodiments, X is C1-3An alkylene group. In some cases, X is CH2、CH2CH2Or CH (CH)3). In different cases, R3Comprising C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group. In some embodiments, R3Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl or pyrimidinyl. In various embodiments, X-R3Selected from the group consisting of:
In some embodiments, X is C ═ O or (C ═ O) O. In various embodiments, R3Comprising C1-6Alkyl or C6-10And (4) an aryl group. In some cases, X-R3Is composed of
In different cases, R4Comprising C3-8Cycloalkyl or C3-9A heterocycloalkyl group. In some embodiments, R4Is composed ofIn various embodiments, R4Comprising C6-10Aryl or C2-9Heteroaryl, and R4Optionally substituted with 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy, C (O) N (R)N)2And N (R)N)2Is substituted with a group of (A), and each RNIndependently is H or C1-3An alkyl group. In some embodiments, R4Selected from the group consisting of: in various embodiments, R4Is composed of
In some embodiments, Ra、Rb、R1aAnd R1bEach is H; r1Is ═ CH2Or CH3;R2Is composed of X-R3Is isobutyl, R4Is composed ofAnd each Y is SO2。
In some embodiments, R1In the (S) conformation.
Also provided herein are compounds listed in table a, table B, and pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a compound selected from the group consisting of:
also provided herein is a pharmaceutical composition comprising a compound of formula (I), a compound listed in table a, a compound listed in table B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Also provided herein is a method of inhibiting protein secretion in a cell comprising contacting a cell with an effective amount of the compound or salt of formula (I), a compound listed in table a or a pharmaceutically acceptable salt thereof, a compound listed in table B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein to inhibit secretion. In some cases, the contacting comprises administering the compound or composition to a subject.
Also provided herein is a method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of a compound or salt of formula (I), a compound listed in table a or a pharmaceutically acceptable salt thereof, a compound listed in table B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
Also provided herein is a method of treating or preventing cancer or a precancerous condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt of formula (I), a compound listed in table a or a pharmaceutically acceptable salt thereof, a compound listed in table B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
Further aspects and advantages will be apparent to those of ordinary skill in the art from a reading of the following detailed description when taken in conjunction with the drawings. The following description includes specific embodiments with the understanding that the present disclosure is to be considered as illustrative, and is not intended to limit the invention to the specific embodiments described herein.
Drawings
Figure 1 depicts B16F10 efficacy data for compound a87 compared to anti-PD-1 therapy. Compound a87 exhibited superior efficacy in terms of tumor growth inhibition and percent body weight in a refractory model relative to once weekly dosing of anti-PD-1 therapy.
Further aspects and advantages will be apparent to those of ordinary skill in the art. While the compounds and methods disclosed herein are susceptible of embodiment in various forms, the following description includes specific embodiments with the understanding that the present disclosure is illustrative, and is not intended to limit the invention to the specific embodiments described herein.
Detailed Description
Provided herein is a compound that inhibits protein secretion. The compounds described herein are useful for treating or preventing diseases associated with excessive protein secretion, such as inflammation and cancer, to improve the quality of life of affected individuals.
The compounds described herein have the structure of formula (I)
Wherein such substituents are described in detail below.
Without being bound by any particular theory, the compounds described herein inhibit protein secretion by binding and disabling a translocon component, including but not limited to Sec61, and in some cases, disrupting the sequence-specific interaction between the nascent signal sequence of the translated protein and the translocon component (including but not limited to Sec 61). The compounds described herein can specifically bind to this signal sequence with little interaction with the translocon itself.
The compounds described herein may be useful for inhibiting TNF α secretion, IC50At most 5. mu.M, or at most 3. mu.M, or at most 1. mu.M. In various instances, the compounds described herein can inhibit IL-2 secretion, IC50At most 5. mu.M, or at most 3. mu.M, or at most 1. mu.M. In some cases, the compounds described herein can inhibit the secretion, IC, of PD-150At most 5. mu.M, or at most 3. mu.M, or at most 1. mu.M.
The compounds described herein are effective in reducing tumor growth and body weight. For example, compound a87 administered once a week in a refractory model may show superior efficacy in reducing tumor growth compared to anti-PD-1 therapy. See the examples section and figure 1.
Chemical definition
As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups containing from one to thirty carbon atoms, such as from one to twenty carbon atoms or from one to ten carbon atoms. Term CnMeaning that the alkyl group has "n" carbon atoms. For example, C4Alkyl refers to an alkyl group having 4 carbon atoms. C1-7Alkyl refers to alkyl groups having a number of carbon atoms that encompasses the entire range (i.e., 1 to 7 carbon atoms) as well as all subgroups (e.g., 1-6, 2-7, 1-5, 3-6, 1,2,3,4, 5,6, and 7 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, n-butyl, n,Isopropyl, n-butyl, isobutyl (2-methylpropyl), tert-butyl (1, 1-dimethylethyl), 3-dimethylpentyl and 2-ethylhexyl. Unless otherwise indicated, alkyl groups may be unsubstituted alkyl groups or substituted alkyl groups.
As used herein, the term "alkylene" refers to a divalent saturated aliphatic group. Term CnMeaning that the alkylene group has "n" carbon atoms. For example, C1-6Alkylene refers to alkylene having a plurality of carbon atoms that encompasses the full range and all subgroups as previously described with respect to "alkyl".
As used herein, the term "alkenyl" is defined identically to "alkyl" except for having at least one carbon-carbon double bond and having from 2 to 30 carbon atoms, for example from 2 to 20 carbon atoms. Term CnMeaning that the alkenyl group has "n" carbon atoms. E.g. C4Alkenyl refers to an alkenyl group having 4 carbon atoms. C2-7Alkenyl refers to alkenyl groups having a plurality of carbon atoms that encompasses the entire range (i.e., 2 to 7 carbon atoms) as well as all subgroups (e.g., 2-6, 2-5, 3-6, 2,3,4, 5,6, and 7 carbon atoms). Specifically contemplated alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, and butenyl. Unless otherwise indicated, alkenyl groups may be unsubstituted alkenyl groups or substituted alkenyl groups.
As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group. Term CnMeaning that the cycloalkyl group has "n" carbon atoms. For example, C5Cycloalkyl refers to cycloalkyl having 5 carbon atoms in the ring. C5-8Cycloalkyl refers to cycloalkyl groups having a plurality of carbon atoms that encompass the entire range (i.e., 5 to 8 carbon atoms) as well as all subgroups (e.g., 5-6, 6-8, 7-8, 5-7, 5,6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, cycloalkyl groups may be unsubstituted cycloalkyl groups or substituted cycloalkyl groups.
As used herein, the term "cycloalkenyl" is defined identically to "cycloalkyl," except thatContaining at least one carbon-carbon double bond, but not aromatic. Term CnDenotes a cycloalkenyl group having "n" carbon atoms. E.g. C5Cycloalkenyl refers to a cycloalkenyl group having 5 carbon atoms in the ring structure. C5-8Cycloalkenyl refers to cycloalkenyl groups having multiple carbon atoms encompassing the entire range (i.e., 5 to 8 carbon atoms) as well as all subgroups (e.g., 5-6, 6-8, 7-7, 5,6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise indicated, cycloalkenyl groups can be unsubstituted cycloalkenyl or substituted cycloalkenyl.
As used herein, the term "heterocycloalkyl" is defined in a similar manner as cycloalkyl, although the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, or sulfur. Non-limiting examples of heterocycloalkyl groups include pyridine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, oxazepan-yl, and the like. Cycloalkyl and heterocycloalkyl groups may be saturated or partially unsaturated ring systems optionally substituted, for example, with one to three groups, independently selected alkyl, alkylene OH, C (O) NH2、NH2Oxo (═ O), aryl, haloalkyl, halogen, and OH. Heterocycloalkyl optionally may be further N-substituted.
As used herein, the term "aryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) carbocyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, biphenyl, indanyl, indenyl, anthracenyl, fluorenyl, tetrahydrolinyl (tetralinyl). Unless otherwise indicated, an aryl group can be an unsubstituted aryl group or a substituted aryl group.
As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) aromatic ring system in which from one to four ring atoms are selected from oxygen, nitrogen, or sulfur, and the remaining ring atoms are carbon, the ring system being joined to the rest of the molecule through any ring atom. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, triazinyl, triazolyl, purinyl, pyrazinyl, purinyl, indolinyl, phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridyl, indolyl, 3H-indolyl, pteridinyl, and quinoxalinyl. Unless otherwise indicated, a heteroaryl group can be an unsubstituted heteroaryl group or a substituted heteroaryl group.
As used herein, the term "hydroxy" or "hydroxyl" is used herein to refer to an "-OH" group.
As used herein, the term "alkoxy" or "alkoxy" refers to "-O-alkyl".
The term "halogen", as used herein, is defined as fluoro, chloro, bromo and iodo.
As used herein, the term "carboxyl" or "carboxyl" refers to the "-COOH" group.
As used herein, the term "amino" refers to the group "-NH2"or" -NH- "group, wherein any hydrogen may be substituted by alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
A "substituted" functional group (e.g., alkyl, alkylene, cycloalkyl, aryl, or heteroaryl) is a functional group having at least one hydrogen group substituted with a non-hydrogen group (i.e., a substituent). Examples of non-hydrogen radicals (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, heteroaryl, heterocycloalkyl, hydroxyl, oxy (or pendant oxy), alkoxy, ester, thioester, acyl, carboxylic acid, cyano, nitro, amino, amido, sulfur, and halogen. When the substituted alkyl group contains more than one non-hydrogen group, the substituents may be bonded to the same carbon or two or more different carbon atoms.
Protein secretion inhibitor
In one aspect, the compounds of the invention have the structure of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
Raand RbEach independently is H or C1-3An alkyl group;
R1is H, OH, C1-3Alkyl, OC1-3Alkyl, ═ CH2Or as NOR5(ii) a Or R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl and forms a spiro ring group with the ring carbon to which it is attached;
R1aand R1bEach independently is H or C1-3An alkyl group;
R2is C1-6Alkyl, N (R)5)2、C3-8Cycloalkyl radical, C3-9Heterocycloalkyl radical, C3-9Heterocycloalkenyl or C6-10An aryl group;
R3is H, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group;
R4is C3-8Cycloalkyl radical, C3-9Heterocycloalkyl radical, C6-10Aryl or C2-9A heteroaryl group;
each R5Independently H, C1-3Alkyl or C0-2alkylene-C6-10An aryl group;
x is absent, C1-3Alkylene, C ═ O, or (C ═ O) O;
y is SO or SO2;
Each heterocycloalkyl, heterocycloalkenyl, and heteroaryl independently has 1,2, or 3 ring heteroatoms selected from N, O and S.
In some embodiments, each Y is SO. In various embodiments, each Y is SO2。
In different cases, RaIs H. In some cases, RaIs C1-3An alkyl group. In some embodiments, RaIs CH3. In some embodiments, RbIs H. In various embodiments, RbIs C1-3An alkyl group. In different cases, RbIs CH3. In some cases, RaAnd RbAre all H.
In some cases, R1Is H, OH or NOR5. In different cases, R5Is H or CH3. Thus, R is suitable1The radicals may comprise H, OH, ═ NOH and ═ NORCH3. In some embodiments, R1Is C1-3Alkyl or OC1-3An alkyl group. For example, R1Can be CH3Or OCH3. In some cases, R1Is CH3And exhibits S stereochemistry. In various embodiments, R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl, and forms a spiro ring group with the ring carbon to which it is attached. Suitable R1The spiro ring group may contain In different cases, R1Is ═ CH2. In some embodiments, R1aAnd R1bEach is H. In some embodiments, R1aAnd R1bAt least one of them is C1-3An alkyl group. In some embodiments, R1aAnd R1bEach is CH3. In some embodiments, RaIs H, RbIs H, and R1Is CH3. In various embodiments, RaIs CH3,RbIs H, andR1is H. In some cases, RaIs H, RbIs CH3And R is1Is H. In different cases, RaIs CH3,RbIs H, and R1Is CH3. In some embodiments, RaIs H, RbIs CH3And R is1Is CH3. In various embodiments, RaIs CH3,RbIs CH3And R is1Is H.
In some embodiments, R2Is C1-6Alkyl or N (R)5)2. In some cases, each R5Independently comprise H, C1-3Alkyl or benzyl. Suitable R2The groups may comprise Et, iPr, N (CH)3)2、 In some cases, R2Comprising C3-8A cycloalkyl group. In different cases, R2Including cyclopentyl or cyclohexyl. In some embodiments, R2Is C3-9Heterocycloalkyl or C3-9A heterocycloalkenyl group. In various embodiments, R2Including oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, or tetrahydropyridinyl. In various embodiments, C3-9Heterocycloalkyl or C3-9Heterocycloalkenyl groups comprise a bridging group or a spiro group. In some cases, said C comprising a bridging or spiro group3-9The heterocycloalkyl group being selected fromAndand R is6Is C1-6Alkyl radical, C3-8Cycloalkyl or C6-10And (4) an aryl group. In some cases, R6Is optionally substituted by 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy and phenyl substituted by the group of CN.
In some cases, R2Selected from the group consisting of: in different cases, R2Is C6-10And (4) an aryl group. In some embodiments, R2Is composed of
In various embodiments, X is absent. In some embodiments, R3Comprising C1-6Alkyl or H. In some cases, R3Is C1-6Alkyl groups such as methyl, ethyl, propyl, butyl, pentyl or hexyl. In some cases, R3Is 2-methylbutyl, isopropylIsopentyl group, CH2CH2OCH3、CH2C(CH3)2CN、CH2CF3Or CH2CH2CF3. In different cases, R3Is an isobutyl group.
In some embodiments, X is C1-3An alkylene group. In some cases, X is CH2、CH2CH2Or CH (CH)3). In different cases, R3Comprising C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group. In some embodiments, R3Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl or pyrimidinyl. Suitable X-R3Examples include In some cases, X-R3Is composed of In some cases, X-R3Is composed of
In some embodiments, X is C ═ O or (C ═ O)O) O. In various embodiments, R3Comprising C1-6Alkyl or C6-10And (4) an aryl group. In some cases, X-R3Is composed of
In different cases, R4Comprising C3-8Cycloalkyl or C3-9Heterocycloalkyl radicals, such as In various embodiments, R4Comprising C6-10Aryl or C2-9Heteroaryl, and R4Optionally substituted with 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy, C (O) N (R)N)2And N (R)N)2Is substituted with a group of (A), and each RNIndependently is H or C1-3An alkyl group. In some embodiments, R4Selected from the group consisting of: in various embodiments, R4Is composed of
In some embodiments, Ra、Rb、R1aAnd R1bEach is H, R1Is ═ CH2Or CH3;R2Is composed of X-R3Is isobutyl, R4Is composed ofAnd each Y is SO2. In some cases, R1In the (S) conformation. In some cases, provided herein includes
A compound of structure (la) wherein R2Is composed of And R is3Is cyclobutyl, cyclopentyl or cyclohexyl.
Examples of compounds of formula (I) are compound a1-a210 shown in table a or a pharmaceutically acceptable salt thereof. In some cases, the compound is compound A1-a151 or a pharmaceutically acceptable salt thereof.
TABLE A
In some embodiments, the compounds of the invention include:
Other compounds of the invention are compounds B1-B22 shown in table B, or a pharmaceutically acceptable salt thereof. In some cases, the compound is compound B1-B20 or a pharmaceutically acceptable salt thereof.
TABLE B
With one or more dashed and thick lines (i.e. withAnd) The chemical structure of the depicted stereocenter is intended to indicate the absolute stereochemistry of the stereocenter present in the chemical structure. The keys indicated by simple lines do not indicate a stereoscopic bias. Unless indicated to the contrary, chemical structures comprising one or more stereocenters, illustrated herein but not indicative of absolute or relative stereochemistry, encompass all possible stereoisomeric forms (e.g., diastereomers, enantiomers) of the compounds and mixtures thereof. Structures with a single bold or dashed line and at least one other simple line encompass a single enantiomeric series of all possible diastereomers.
Synthesis of protein secretion inhibitors
The compounds provided herein can be synthesized using conventional techniques and readily available starting materials known to those skilled in the art. In general, the compounds provided herein are routinely obtained by standard organic chemical synthesis methods.
Synthesis of the final Compound
In some cases, the compounds described herein can be prepared by reacting a compound having the desired R2The sulfonyl chloride of the group is reacted with propane-1, 3-diamine and the resulting product is reacted with a compound having the desired R3The aldehyde of the group reacts to form an N-substituted propylamine compound. The propylamino group may be introduced into R of an N-substituted propylamine by reaction with 2- (3-bromopropyl) isoindoline-1, 3-dione, followed by reaction with hydrazine4In situ and by contacting the compound with menstrual period R4Reacting the group-functionalized sulfonyl chloride to convert the desired R4A moiety is conjugated to the compound. Finally, the compounds may be prepared by reacting a compound having the desired R1Cyclizing a cyclizing agent of the group, such as 3-chloro-2-chloromethyl-1-propene, 2-methylpropane-1, 3-diyl diethyldisulfonate, cyclopropane-1, 1-diylbis (methylene) diethylsulfonate, 1, 3-dichloropropane or 1, 4-dichlorobutane.
In some embodiments, by converting the expected R3And R4Radical-derivatized (3-aminopropyl) propane-1, 3-diamino groups with the desired R2-amine sulfonyl chloride or R2Conjugation of the sulfonyl chloride group, synthesizable in R1A compound having a methylene group, and then reacting the resulting compound with 3-chloro-2-chloromethyl-1-propene to form the desired triazacyclododesulfonamide (triazacyclodocanesulfonamide) compound, as exemplified in pathway 1 in the examples section.
In various embodiments, the synthesis is at R1The compounds having a methylene group can be prepared by reacting a protected butane-1, 3-diamine with a compound having the desired R3Aldehyde conjugation of the group to form 3- (azenyl) -N-butan-1-amine (3- (azanyl) -N-butan-1-amine), such that R2Amino in position with menstrual periscope R2Group-functionalized chloro groups, introduction of the propylamino group into the R of 3- (azepinyl) -N-butan-1-amine by reaction with 2- (3-bromopropyl) isoindoline-1, 3-dione and subsequent reaction with hydrazine4Position (c) so that the resulting R4Position amino group and menstrual periscope R4The group-functionalized chloro group is reacted followed by reaction of the resulting compound with 3-chloro-2-chloromethyl-1-propene to form the desired triazacyclododecanesulfonamide compound, as exemplified in pathway 2 in the examples section.
In some cases, the synthesis is at R1Compounds having spiro ring groups may be prepared by reacting the desired R2、R3And R4Group-derivatized N- (3- (azanyl) propyl) propane-1, 3-diamino groups reacted with 1, 1-diylbis (methylene) diethylsulfonate, derivatized with a prophetic spiro group, as in pathways 3, 8 and 9 of the examples sectionAs exemplified.
In various instances, the synthesis of the compounds provided herein can be accomplished by coupling the desired R3And R4Radical-functionalized N- (3- (azanyl) propyl) propane-1, 3-diamino on R2Reduction of the benzyl group followed by bringing the resulting product into contact with the desired phase R2Group (e.g., dimethylcyclohexyl) derivatized aldehydes, as exemplified in pathway 4 in the examples section.
In some embodiments, at R2Compounds having a carboxylic acid group can be prepared by reacting the desired R1、R3And R4The group-derivatized triazacyclododecanesulfonyl group is reacted with the desired alkyl group and triphosgene under basic conditions, as exemplified in route 5 in the examples section.
In various embodiments, at R2Compounds having piperidinyl groups can be prepared by reacting DBU/mercaptoethanol with a compound having the desired R1、R3And R4Group and in R2A triazacyclododecanesulfonyl compound functionalized with a nitrophenyl group is reacted and the resulting product is then conjugated with a piperidinyl sulfonyl chloride as exemplified in route 6 in the examples section.
In some embodiments, at R1Synthesis of a Compound having Hydrogen groups can be carried out by converting the desired R2、R3And R4The group-functionalized N- (3- (azanyl) propyl) propane-1, 3-diamino is conjugated to 1, 3-dichloropropane or 1, 4-dichlorobutane as exemplified by pathway 7 and pathway 17 of the examples section.
In some cases, at R2The compounds having a chlorophenyl methanone group can be synthesized by reacting R1、R3And R4The group-functionalized triazacyclododecanesulfonyl group is reacted with 4-chlorobenzoyl chloride under basic conditions, as exemplified in pathway 10 in the examples section.
In different cases, at R4Having a 4- (dimethylamino) -2-methylbenzyl group and at R1Compounds having spiro ring groups may be prepared by reacting the desired R2And R3The group-functionalized N- (3- (azanyl) propyl) propane-1, 3-diamino compound is reacted with 4- (dimethylamino) -2-tosyl chloride, followed by cyclization of the compound via conjugation to 1, 1-diylbis (methylene) diethylsulfonate derivatized with a desired spiro ring group using methods previously described herein, as exemplified by pathway 11 in the examples section.
In some embodiments, the compounds described herein can be prepared by reacting a compound having the desired R2The sulfonyl chloride of the group is reacted with propane-1, 3-diamine and the resulting product is reacted with a compound having the desired R3The aldehyde of the group reacts to form a 3- (azanyl) -N-butan-1-amine compound. The propylamino group can be introduced into the R of 3- (azanyl) -N-butan-1-amine by reaction with 2- (3-bromopropyl) isoindoline-1, 3-dione and subsequent reaction with hydrazine4In position, and the desired R can be made by reacting the compound with the desired sulfonyl chloride (e.g., 4- (dimethylamino) -2-toluenesulfonyl chloride)4The moiety is conjugated to the compound. Finally, the compound can be cyclized via a suitable cyclizing agent, such as 3-chloro-2-chloromethyl-1-propene, 2-methylpropane-1, 3-diyl disulfonate, cyclopropane-1, 1-diylbis (methylene) diethylsulfonate, 1, 3-dichloropropane, or 1, 4-dichlorobutane as previously described herein, as exemplified in pathway 12 in the examples section.
In various embodiments, at R2Synthesis of Compounds having a 4-Phenylpiperidin-1-ylsulfonyl group1、R3And R4The group-functionalized triazacyclododecanesulfonyl group is reacted with 3-methyl-1- ((4-phenylpiperidin-1-yl) sulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate as exemplified in pathway 14 in the examples section.
In some cases, at R2Synthesis of Compounds having a 4-Phenylpiperidin-1-ylsulfonyl group3And R4Group-functionalized N- (3- (azanyl) propyl) propane-1, 3-diamino is reacted with 3-methyl-1- ((4-phenylpiperidin-1-yl) sulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate, followed by reaction with a suitable cyclizing agent (such as the previously described 2-methylpropane-1, 3-diyl diethylsulfonate herein, a salt thereof, a base,3-chloro-2-chloromethyl-1-propene, cyclopropane-1, 1-diylbis (methylene) diethylsulfonate, 1, 3-dichloropropane, or 1, 4-dichlorobutane) this compound is cyclized as exemplified in pathway 15 in the examples section. Having a radical of formula (I) with R4Analogous compounds to the nitrogen-adjacent methyl group can be synthesized using 3-chloro-2- (chloromethyl) prop-1-ene as well, as exemplified in pathway 18 in the examples section.
In some cases, R1Synthesis of compounds having an alcohol group can be achieved by cyclizing an N- (3- (azanyl) propyl) propane-1, 3-diamino compound with protected 1, 3-dichloropropan-2-ol under basic conditions, as exemplified in pathway 19 in the examples section. At R1The alcohol group of (a) can be methylated via reaction with MeI and NaH in toluene, as exemplified in pathway 21 in the examples section. At R1The alcohol group of (a) can be oxidized to a carbonyl group via reaction with dess-martin periodinane, as exemplified in pathway 22 in the examples section. At R1Can be reacted with hydroxylamine hydrochloride to form oxime compounds, as exemplified in pathway 25 in the examples section.
In different cases, at R1Synthesis of compounds having S-methyl groups can be achieved by reacting the desired R2Group-functionalized amino groups were reacted with 2, 3-dimethyl-1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate, followed by CF3SO3Me to form the desired R2Group-functionalized 2, 3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. The product can be used with menstrual period observation R4(R) -N- (3-amino-2-methylpropyl) group-functionalized to form the desired R2And R4Radical-functionalized (S) -N, N' - (2-methylpropane-1, 3-diamino the resulting product can then be reacted with a menstrual charge R3The group-functionalized dimethanesulfonic acid (azaalkanediyl) bis (propane-3, 1-diyl) ester reacts to give the desired compound, as exemplified in pathway 27 in the examples section.
Synthesis of intermediates
Intermediates used to prepare the compounds described herein can also be prepared by standard methods known to those skilled in the art, as described in the examples section below (e.g., pathway 13, pathway 16, pathway 20, pathway 24, pathway 26, pathway 28, pathway 30, pathway 31, pathway 32, pathway 33).
Method of use
The compounds disclosed herein (e.g., the compounds of formula (I), the compounds listed in tables a and B, and the pharmaceutically acceptable salts of the foregoing compounds) inhibit protein secretion of a protein of interest. The compounds disclosed herein can interfere with the Sec61 protein secretion machinery of cells. In some cases, a compound disclosed herein inhibits secretion of one or more of TNF α, VCAM, PRL, IL-2, INFg, CD4, insulin, and PD-1 (mouse and/or human), or inhibits secretion of each of TNF α, VCAM, PRL, IL-2, INFg, CD4, insulin, and PD-1 (mouse and/or human). In some cases, the compounds disclosed herein can inhibit the secretion of checkpoint proteins, or inhibit cell surface proteins, endoplasmic reticulum-associated proteins, or secreted proteins involved in the regulation of anti-tumor immune responses. In various instances, a compound disclosed herein can inhibit secretion of one or more of PD-1, PD-L1, TIM-1, LAG-3, CTLA4, BTLA, OX-40, B7H1, B7H4, CD137, CD47, CD96, CD73, CD40, VISTA, TIGIT, LAIR1, CD160, 2B4, TGFR β, and combinations thereof. Protein secretion activity can be assessed in the manner described in the examples section below.
As used herein, the term "inhibitor" is intended to describe a compound that blocks or reduces the activity of a pharmacological target (e.g., a compound that inhibits the function of Sec61 in the protein secretion pathway). Inhibitors may act in a competitive, noncompetitive or noncompetitive manner. Inhibitors may bind in a reversible or irreversible manner, and thus the term encompasses compounds that are suicide substrates for proteins or enzymes. The inhibitor may modify one or more sites at or near the active site of the protein, or it may cause a structural change at other sites on the enzyme. The term inhibitor is used more broadly herein than the scientific literature to also encompass other classes of pharmacologically or therapeutically useful agents, such as agonists, antagonists, stimulators, and cofactors, and the like.
Accordingly, provided herein are methods of inhibiting protein secretion in a cell. In these methods, the cell is contacted with a compound described herein (e.g., a compound of formula (I), or a compound listed in table a or B, and pharmaceutically acceptable salts of the foregoing compounds), or a pharmaceutical formulation thereof, in an amount effective to inhibit secretion of the protein of interest. In some embodiments, the cell is contacted in vitro. In various embodiments, the cell is contacted in vivo. In various embodiments, the contacting comprises administering the compound or pharmaceutical formulation to the subject.
The biological consequences of Sec61 inhibition are numerous. For example, Sec61 inhibition has been proposed for use in treating or preventing inflammation and/or cancer in a subject. Thus, pharmaceutical formulations of Sec 61-specific compounds provide a means for administering drugs to subjects and treating these conditions. As used herein, the terms "treat", "treating" and "treatment" and the like refer to the elimination, reduction or amelioration of a disease or condition and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat", "treating", and "treatment", etc., may include "prophylactic treatment", which refers to reducing the likelihood of reoccurrence of a disease or condition, or the likelihood of recurrence of a previously controlled disease or condition, in a subject who does not have the disease, but is at risk or susceptible to reoccurrence, or who is at risk or susceptible to reoccurrence. The terms "treatment" and synonyms contemplate administration of a therapeutically effective amount of a compound of the invention to a subject in need of such treatment. Within the meaning of the present invention, "treatment" also includes relapse prevention or stage prevention, as well as treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment may be symptomatic, e.g., suppression of symptoms. It may function for a short period of time, for a medium period of time, or may be a long-term treatment, for example in the case of maintenance therapy. As used herein, the terms "prevent", "preventing", "prevention" are art-recognized and are well known when used in connection with conditions such as local recurrence (e.g., pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition, and include administration of a composition that reduces the frequency of symptoms of a medical condition in a subject or delays the onset of symptoms of a medical condition in a subject relative to a subject not receiving the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a patient cohort receiving prophylactic treatment relative to an untreated control cohort, and/or delaying the appearance of detectable cancerous growths, for example, in a statistically and/or clinically significant amount in a treatment cohort versus an untreated control cohort. Prevention of infection includes, for example, reducing the number of diagnoses of infection in the treated versus untreated control group, and/or delaying the onset of symptoms of infection in the treated versus untreated control group. Prevention of pain includes, for example, reducing the magnitude of pain experienced by the subject or delaying the pain sensation experienced by the subject in the treated versus untreated control group. As used herein, the terms "patient" and "subject" are used interchangeably and refer to animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals), as well as humans. A particular patient is a mammal (e.g., a human). The term patient includes males and females.
Inhibition of Sec 61-mediated secretion of inflammatory proteins (e.g., TNF α) may disrupt signaling of speech. Thus, provided herein is a method of treating inflammation in a subject by administering to the subject a therapeutically effective amount of a compound described herein (i.e., a compound of formula (I) or a compound listed in table a or B, or a pharmaceutically acceptable salt of the foregoing).
In addition, the viability of cancer cells is dependent on increased secretion of proteins into the ER for survival. Thus, non-selective or partially selective inhibition of protein secretion mediated by Sec61 may inhibit tumor growth. Alternatively, in an immuno-oncology setting, it is known that selective secretory inhibitors of secretory or transmembrane immune checkpoint proteins (e.g., PD-1, TIM-3, LAG3, etc.) can lead to activation of the immune system to combat various cancers.
Thus, also provided herein is a method of treating cancer in a subject by administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), a compound listed in table a or B, or a pharmaceutically acceptable salt of the foregoing). Cancers particularly envisioned that may be treated using the compounds and compositions described herein include, but are not limited to, melanoma, multiple myeloma, prostate cancer, lung cancer, non-small cell lung cancer, squamous cell carcinoma, leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphoma, NPM/ALK-transformed anaplastic large cell lymphoma, diffuse large B-cell lymphoma, neuroendocrine tumors, breast cancer, mantle cell lymphoma, renal cell carcinoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, small cell carcinoma, adenocarcinoma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, thyroid cancer, anaplastic large cell lymphoma, hemangioma, head and neck cancer, bladder cancer, and colorectal cancer. In some cases, the cancer is a solid tumor. In various cases, the cancer is head and neck cancer, squamous cell carcinoma, gastric cancer, or pancreatic cancer.
The compounds described herein are also envisioned to be used in the prevention and/or treatment of a wide variety of diseases, including but not limited to proliferative, neurotoxic/degenerative diseases, ischemic conditions, autoimmune and autoinflammatory diseases, inflammation, immune related diseases, HIV, cancer, organ transplant rejection, septic shock, viral and parasitic infections, conditions associated with acidosis, maculopathy, pulmonary diseases, muscle wasting diseases, fibrotic diseases, bone and hair growth diseases.
Examples of proliferative diseases or conditions include diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congestive heart failure, scleroderma, radiation fibrosis, and pulmonary fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease, sarcoidosis, interstitial lung disease, and extrinsic lung disorders).
Inflammatory diseases include acute conditions (e.g., bronchitis, conjunctivitis, myocarditis, pancreatitis) and chronic conditions (e.g., chronic cholecystitis, bronchiectasis, aortic stenosis, vascular restenosis, psoriasis, and arthritis), as well as conditions associated with inflammation, such as fibrosis, infection, and ischemia.
Immunodeficiency disorders occur when a portion of the immune system fails to function properly or is absent. It may affect B lymphocytes, T lymphocytes or phagocytes, and may be congenital (e.g., IgA deficiency, Severe Combined Immunodeficiency (SCID), thymic dysplasia and chronic granulomatosis) or acquired (e.g., acquired immunodeficiency syndrome (AIDS), acquired immunodeficiency syndrome (HIV) and drug-induced immunodeficiency). Immune related conditions include allergic disorders such as allergy, asthma and eczema, which is an atopic dermatitis. Other examples of such immune-related conditions include lupus erythematosus, rheumatoid arthritis, scleroderma, ankylosing spondylitis, dermatomyositis, psoriasis, multiple sclerosis, and inflammatory bowel disease (such as ulcerative colitis and crohn's disease).
Tissue/organ transplant rejection occurs when the immune system mistakenly attacks cells introduced into the host. Graft Versus Host Disease (GVHD) caused by allogeneic transplantation occurs when T cells from donor tissue become aggressive and attack host tissue. In all three cases, autoimmune diseases, transplant rejection and GVHD, it may be beneficial to modulate the immune system by treating the subject with a compound or composition of the invention.
Also provided herein are methods of treating an autoimmune disease in a patient comprising administering a therapeutically effective amount of a compound described herein. As used herein, an "autoimmune disease" is a disease or disorder that arises from and is directed against the subject's own tissue. Examples of autoimmune diseases include, but are not limited to, inflammatory reactions, such as inflammatory skin diseases, including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including Adult Respiratory Distress Syndrome (ARDS)); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory reactions; atherosclerosis; white blood cell adhesion defect; rheumatoid arthritis; systemic Lupus Erythematosus (SLE); diabetes (e.g., type I diabetes or insulin dependent diabetes); multiple sclerosis; reynaud's syndrome; autoimmune thyroiditis; allergic encephalomyelitis; sjorgen's syndrome; juvenile onset diabetes; and the immune response associated with acute and delayed hypersensitivity mediated by cytokines and T lymphocytes commonly found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia (Addison's disease); diseases involving leukocyte extravasation; central Nervous System (CNS) inflammatory disorders; multiple organ injury syndrome; hemolytic anemia (including, but not limited to, cryoglobinemia (cryoglobinemia) or Coombs positive anemia (Coombs positive anemia)); myasthenia gravis; antigen-antibody complex-mediated diseases; resistance to glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; graves' disease; Lambert-Eaton myasthenia gravis syndrome; bullous pemphigoid; pemphigus; autoimmune polyendocrine gland disease; leiter's disease; stiff-man syndrome (stiff-man syndrome); beheet disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathy; immune Thrombocytopenic Purpura (ITP) or autoimmune thrombocytopenia. Accordingly, the compounds provided herein are useful in the treatment of disorders associated with inflammation, including but not limited to COPD (chronic obstructive pulmonary disease), psoriasis, asthma, bronchitis, emphysema, and cystic fibrosis.
The invention also provides the use of a compound described herein for the treatment of neurodegenerative diseases. Neurodegenerative diseases and conditions include, but are not limited to: stroke, ischemic injury of the nervous system, nerve trauma (e.g., stroke brain injury, spinal cord injury, and traumatic injury of the nervous system), multiple sclerosis and other immune-mediated neuropathies (e.g., Gulian-Barre Syndrome and variants thereof, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy and Fisher Syndrome), HIV/AIDS dementia complex, axonopathy (axomicy), diabetic neuropathy, Parkinson's disease, Huntington's disease, multiple sclerosis, bacterial, parasitic, fungal and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, dementia with Lewy bodies (Lewy body dementias), frontopal dementia such as Pick's disease, subcortical dementia such as Huntington's or progressive supranuclear palsy, Cortical atrophy syndrome (such as primary aphasia), metabolic toxicity dementia (such as chronic hypothyroidism or B12 deficiency), and dementia caused by infection (such as syphilis or chronic meningitis).
Further guidance for inhibiting protein secretion using the compounds and compositions described herein (e.g., compounds of formula (I), compounds listed in tables a or B, or pharmaceutically acceptable salts of the foregoing compounds) can be found in the examples section below.
Pharmaceutical formulations and administration
The methods provided herein include the manufacture and use of pharmaceutical compositions comprising one or more compounds provided herein. In addition, the pharmaceutical composition itself is also included. The pharmaceutical composition typically comprises a pharmaceutically acceptable carrier. Accordingly, provided herein are pharmaceutical formulations comprising a compound as described herein before (e.g., a compound of formula (I), a compound listed in table a or B, or a pharmaceutically acceptable salt of the foregoing compound) as described herein before, and one or more pharmaceutically acceptable carriers.
The phrase "pharmaceutically acceptable" refers herein to ligands, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the phrase "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) no pyrogen water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials for use in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are non-pyrogenic, i.e., do not cause a significant temperature increase when administered to a patient.
The term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds provided herein. These salts may be prepared in situ during the final isolation and purification of the compounds provided herein, or separately by reacting the compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative Salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthenate (naphylate), methanesulfonate, glucoheptonate, lactate (lactobionate), laurylsulfonate, and amino acid Salts and the like (see, e.g., Berge et al, (1977) "Pharmaceutical Salts", j.pharm.sci.66: 1-19).
In some embodiments, the compounds provided herein may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable" in these examples refers to the relatively non-toxic inorganic and organic base addition salts of the compounds provided herein. These salts can also be prepared in situ during the final isolation and purification of the compound, or separately by reacting the purified compound in its free, free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al, supra).
Wetting agents, emulsifying agents and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.
As is well known in the art, the compositions prepared as described herein may be administered in various forms depending on the disorder to be treated and the age, condition, and weight of the patient. For example, where the composition is to be administered orally, the composition may be formulated as a tablet, capsule, granule, powder, or syrup; or parenterally, the compounds may be formulated as injections (intravenous, intramuscular, or subcutaneous), instillations, or suppositories. For application via the ophthalmic mucosal route, the compounds may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means in conjunction with the methods described herein, and the active ingredient may be mixed with any conventional additive or excipient, such as a binder, disintegrant, lubricant, flavoring agent, solubilizing agent, suspension aid, emulsifier, or coating agent, if desired.
The actual dosage level of the active ingredient in the pharmaceutical compositions of this invention can be varied to obtain a "therapeutically effective amount" of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.
The concentration of a compound provided herein in a pharmaceutically acceptable mixture will vary depending on a number of factors, including the dose of the compound to be administered, the pharmacokinetic properties of the compound used, and the route of administration. In some embodiments, the compositions provided herein can be provided in the form of an aqueous solution comprising about 0.1-10% w/v of a compound disclosed herein, among other materials, for parenteral administration. Typical dosages range from about 0.01 to about 50 mg/kg body weight per day, given in 1-4 divided doses. Each divided dose may contain the same or different compounds. The dosage will be a therapeutically effective amount, which will depend on a number of factors including the overall health of the patient and the formulation and route of administration of the compound selected.
Dosage forms or compositions may be prepared containing in the range of 0.005% to 100% of a compound of the invention with the remainder being a non-toxic carrier. Methods for preparing these compositions are well known to those skilled in the art. Contemplated compositions may contain from 0.001% to 100%, in one embodiment from 0.1% to 95%, and in another embodiment from 75% to 85% active ingredient. Although the dosage will vary according to the patient's symptoms, age and weight, the nature and severity of the condition to be treated or prevented, the route and form of administration of the drug, in general, for adult patients, daily dosages of from 0.01 to 2000 mg of the compound are recommended, and this may be administered in a single dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
In the right to forbid patenting of methods practiced on the human body, the meaning of "administering" a composition to a human subject should be limited to prescribing a control substance to be self-administered by the human subject via any technique (e.g., oral, inhalation, surface application, injection, insertion, etc.). Compliance with the broadest reasonable interpretation of the law or regulation that defines patentable subject matter is required. In the right not to forbid the patent rights granted to the method of practice on the human body, "administering" the composition includes the method of practice on the human body as well as the aforementioned activities.
Other embodiments
It is to be understood that while the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
Examples
The following examples are provided for illustration and are not intended to limit the scope of the invention.
Route 1
The starting material was synthesized using the method described in j.med.chem.2016,59, 2633-2647. To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4-toluenesulfonamide (0.200g,0.523mmol) in DCM (2.0mL) was added DIEA (2eq,1.05mmol,179uL) and subsequently piperidine-1-sulfonyl chloride (0.096g,0.523 mmol). After 16 h, the reaction was quenched with sodium bicarbonate (saturated), extracted with DCM, dried over sodium sulfate, filtered, and concentrated.
To a solution of crude N- (3- ((cyclohexylmethyl) (3- ((4-methylphenyl) sulfonamido) propyl) amino) propyl) piperidine-1-sulfonamide in DMF (10mL) was added NaH (2.5eq,1.31mmol,0.052g of a 60% dispersion in mineral oil). The mixture was stirred for 1 hour and then heated to 85 ℃ and 3-chloro-2-chloromethyl-1-propene (0.9eq,0.471mmol,55uL dissolved in 0.5mL DMF) was added over 4 hours. After heating for 16 hours, the mixture was cooled to ambient temperature, diluted with brine and water, extracted with ethyl acetate (3 ×), washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-60% hexane/ethyl acetate + 1% DEA) afforded the free base product.
To the free base was added diethyl ether (1.0mL) to dissolve, and HCl (4N dioxane solution, 1.046mmol,262uL) was added. The HCl salt was filtered and dried under high vacuum to give compound a 5. C of MS (EI)29H48N4O4S2Found 581[ M + H]+。
The following compounds were synthesized in a similar manner:
route 2
To (3-Aminobutyl) carbamic acid tert-butyl ester (2.5g,13.3mmol) in DCM (12.5mL) and saturated Na2CO3TsCl (13.3mmol,2.54g) was added to a saturated NaCl solution (12.5 mL). After 1 hour, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give tert-butyl (3- ((4-methylphenyl) sulfonamido) butyl) carbamate, which was used further without further purification.
To the tosylate salt (13.3mmol) was added TFA (66.5mmol,5.09mL) and DCM (5.09 mL). After 2 hours, the reaction was concentrated, diluted with NaOH (1N,30mL), extracted with DCM (3X30mL), dried over sodium sulfate, filtered, and concentrated to give the amine.
To the amine (10.94mmol) was added toluene (49mL) and cyclohexanecarboxaldehyde (1.34g,12.0 mmol). The mixture was refluxed overnight (external temperature 185 ℃) with a dean stark apparatus and then concentrated, diluted with ethanol (absolute, 19mL) and NaBH added portionwise4(0.827g,21.8mmol) while maintaining the internal temperature<At 20 ℃. After stirring for 2 hours, the mixture was diluted with water (10mL), stirred for 20 minutes, extracted with DCM (3 ×), washed with brine, dried over sodium sulfate, filtered, and concentrated to give the amine. The amine was diluted with diethyl ether (20mL) and HCl (concentrated HCl,. about.0.3 mL) was added dropwise. The HCl salt was broken up over 5 minutes and filtered using diethyl ether to wash. The product was dried overnight under vacuum to give N- (4- ((cyclohexylmethyl) amino) but-2-yl) -4-toluenesulfonamide hydrochloride.
To the HCl salt (3.5mmol) were added acetonitrile (9mL), sodium carbonate (0.99g,9.2mmol), LiI (0.114g) and 3-bromopropylphthalimide (2.30 g). The mixture was heated to 70 ℃ for 5 hours, at which point it was filtered and concentrated. The crude phthalimide was used further without further purification.
To the phthalimide (3.5mmol) were added hydrazine monohydrate (4.2mL) and ethanol (15 mL). The reaction was completed after heating to 80 ℃ for 30 minutes, and the precipitate was filtered and washed with ethanol. The filtrate was concentrated and diluted with HCl (2N,30mL), then allowed to stand for 1 hour. To the aqueous mixture was basified to pH 10 by addition of NaOH (1N). The mixture was then extracted with DCM (3 ×), dried over sodium sulfate, filtered, and concentrated to give crude N- (4- ((3-aminopropyl) (cyclohexylmethyl) amino) butan-2-yl) -4-toluenesulfonamide.
To the amine (695mg,1.76mmol) was added DCM (9mL), saturated Na2CO3(9mL), saturated NaCl (9mL), TsCl (1.76mmol,336 mg). After stirring for 1 hour, the mixture was extracted with DCM (3 ×), dried over sodium sulfate, filtered, and concentrated to give the free base. The HCl salt was prepared by diluting the free base in diethyl ether (50mL) and adding HCl (concentrated HCl,300 uL). After being placed under high vacuum for 2 hours, the HCl salt (1.02g) was collected.
To a solution of the HCl salt (0.400g,0.683mmol) in DMF (14mL) was added NaH (3.5eq,2.39mmol, 60% dispersion in mineral oil, 80.3 mg). After stirring for 1 hour, 3-chloro-2-chloromethyl-1-propene (0.9eq,0.615mmol,71uL in 7mL DMF) was added dropwise over 3 hours. After an additional 2 hours of heating, the mixture was cooled to ambient temperature, washed with brine, water and ethyl acetateAnd (6) diluting. The mixture was extracted with ethyl acetate (2 ×), washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-90% hexane/ethyl acetate + 1% DEA) afforded the product. The HCl salt was formed by diluting the free base in diethyl ether (20vol.) and adding HCl (4N dioxane solution, 4eq) to give 5- (cyclohexylmethyl) -2-methyl-11-methylene-1, 9-xylenesulfonyl-1, 5, 9-triazacyclododecane hydrochloride, compound B1. C of MS (EI)32H47N3O4S2Measured value 602[ M + H]+。
The following compounds were synthesized in a similar manner:
route 3
To a solution of N- (3- ((cyclohexylmethyl) (3- ((4-methylphenyl) sulfonamido) butyl) amino) propyl) -4-toluenesulfonamide (0.099mmol) in DMF (10.0mL) was added sodium hydride (0.350mmol of a 60% dispersion in mineral oil). The mixture was stirred at ambient temperature for 30 minutes and then heated to 80 ℃, followed by the addition of cyclopropane-1, 1-diylbis (methylene) diethylsulfonate (0.099mmol, dissolved in 1.0ml dmmf) over a2 hour period. After stirring at 80 ℃ for an additional 4 hours, the mixture was cooled to ambient temperature, quenched with brine and extracted with ethyl acetate (3 ×). The combined organics were washed with brine (2 ×), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-60% hexane (1% DEA)/ethyl acetate) afforded the free base product, which was dissolved in diethyl ether (2mL) and HCl (0.1mL of 4N 1, 4-dioxane) was added. The mixture was concentrated to give 4- { [9- (cyclohexylmethyl) -13- (4-methylbenzenesulfonyl) -5,9, 13-triazaspiro [ 2.11%]Tetradecan-5-yl]Sulfonyl } -N, N-dimethylaniline hydrochloride, compound a 11. C of MS (EI)33H50N4O4S2Found value 631[ M + H]+。
Pathway 4
The starting material was synthesized using the method described in j.med.chem.2016,59, 2633-2647. To a solution of the starting material (0.327mmol) in methanol (2.0mL) was added Pd/C (20 mg). A hydrogen atmosphere was established and the mixture was stirred at ambient temperature. After 3 hours the reaction was filtered and purified by flash column chromatography (0-80% hexane (1% DEA)/ethyl acetate) to give the product.
To this starting material (0.028mmol) was added toluene (5mL) and then aldehyde (0.028 mmol). The mixture was stirred at reflux for 3 hours and then concentrated. To this imine was added ethanol and then sodium borohydride. The mixture was stirred at ambient temperature for 30 minutes, then diluted with water (1mL), extracted with DCM (3X1mL), dried over sodium sulfate, filtered, and concentrated. The product was purified by flash column chromatography (0-60% hexane (1% DEA)/ethyl acetate). The free base was diluted with ether (1mL) and HCl (7. mu.L, 4N dioxane solution) was added. The mixture was filtered to give 4- ((9- ((4, 4-dimethylcyclohexyl) methyl) -3-methylene-5-toluenesulfonyl-1, 5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline hydrochloride (compound a 10). C of MS (EI)34H52N4O4S2Found 645[ M + H]+。
To a solution of triphosgene (0.0316mmol,9.4mg) in DCM (100uL) was added 1-propanol (0.190mmol, 14 uL). After stirring for 45 min the solution was added to amine (0.0158mmol,8.2mg), DIEA (0.126mmol,22uL) and DCM (100 uL). The mixture was stirred at ambient temperature for 1 hour, followed by direct purification by flash column chromatography (0-70% hexane/ethyl acetate) to give 5- ((4- (dimethylamino) phenyl) sulfonyl) -7-ylideneMethyl-9-tosyl-1, 5, 9-triazacyclododecane-1-carboxylic acid propyl ester (Compound A12). C of MS (EI)29H42N4O6S2Found value 607[ M + H]+。
Pathway 6
The starting material, 4- ((9- (cyclohexylmethyl) -3-methylene-5- ((2-nitrophenyl) sulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline, was synthesized using a similar procedure as described in route 2, but with the appropriate sulfonyl chloride.
To a solution of the starting material (1.09g,1.68mmol) in ACN (12.3mL) was added DBU (0.780mL,5.22mmol) and then 2-mercaptoethanol (0.135mL,1.92 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of another aliquot of 2-mercaptoethanol (1.14 eq). After stirring for an additional 2 hours, the mixture was concentrated and directly purified with FCC (0-100% hexane (1% DEA)/ethyl acetate). 4- ((9- (cyclohexylmethyl) -3-methylene-1, 5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline.
To a solution of the amine (70mg,0.152mmol) in DCM (2mL) was added DIEA (0.303mmol,52uL) and then piperidine-1-sulfonyl chloride (0.152mmol,28 mg). After allowing to stand overnight, the reaction was directly purified by flash column chromatography (hexane (1% DEA)/ethyl acetate 0-60%). The HCl salt product was prepared by dissolving the free base in diethyl ether (1mL) and adding HCl (4N dioxane solution, 38 uL). The filtrate was collected to give 4- ((9- (cyclohexylmethyl) -3-methylene-5- (piperidin-1-ylsulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline hydrochloride (compound a 15). C of MS (EI)30H51N5O4S2Measured value 610[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 7
The starting material, N- (3- ((cyclohexylmethyl) (3- ((4- (dimethylamino) phenyl) sulfonamido) propyl) amino) propyl) -4-toluenesulfonamide, was synthesized using the same method described in route 1, but with the appropriate sulfonyl chloride.
To a solution of the diamine (49mg,0.087mmol) in DMF (2.5mL) was added NaH (0.22mmol,9 mg). After stirring for 30 minutes at ambient temperature, 1, 3-dichloropropane (0.087mmol,8.3uL in 0.5mL DMF) was added slowly over 1 hour while heating at 80 ℃. After 3 hours the mixture was cooled to ambient temperature and diluted with brine (10mL), water (5mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 5mL), the organics were combined and washed with brine (1 × 5mL), dried over sodium sulfate, and concentrated. Flash column chromatography (0-50% hexane (1% DEA/ethyl acetate)) afforded the free base product, which was converted to the HCl salt after addition of diethyl ether (1mL) followed by addition of HCl (20uL,4N dioxane solution). The filtrate was collected and concentrated to give 4- ((5- (cyclohexylmethyl) -9-toluenesulfonyl-1, 5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline (compound a 14). C of MS (EI)31H48N4O4S2Measured value 605[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 8
The starting material was synthesized using the method described in j.med.chem.2006,49, 1291-. To a solution of N1- (3-aminopropyl) -N1-benzylpropane-1, 3-diamine (363mg,1.64mmol) in DCM (2mL) was added DIEA (1.14mL,6.56mL) and then sulfonyl chloride (345. mu.L, 2.46 mmol). The solution was allowed to stand overnight at ambient temperature. Concentration and purification by flash column chromatography (0-80% (1% DEA)/ethyl acetate) to give the product.
To a solution of the starting material (260mg,504 μ L) in DMF (20mL) was added NaH (50mg of a 60% dispersion in mineral oil, 1.26 mmol). The mixture was stirred at 80 ℃ for 20 minutes, followed by the addition of the bis-sulfonate salt (144mg,504 μ L) over a1 hour period. The reaction was complete after heating for 4 hours, and was diluted with ethyl acetate (40mL) and brine (40mL) and extracted with ethyl acetate (2X20 mL). The combined organics were washed with brine (20mL), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (hexane (1% DEA)/ethyl acetate 0-50%) afforded the product, which was diluted with ether (5mL) and HCl (4N dioxane solution, 100uL) was added. The mixture was concentrated, washed with diethyl ether, and dried to give 9-benzyl-5, 13-bis (piperidin-1-ylsulfonyl) -5,9, 13-triazaspiro [2.11 ]]Tetradecane hydrochloride (compound a 18). C of MS (EI)28H47N5O4S2Found 581[ M + H]+。
Pathway 9
The starting material, N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4- (dimethylamino) benzenesulfonamide, was synthesized using a similar method as described in pathway 2.
To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4- (dimethylamino) benzenesulfonamide (559mg,1.36mmol) in DCM (2mL) was added DIEA (0.71mL,4.08mmol) and then sulfonyl chloride (250mg,1.36 mmol). The solution was allowed to stand overnight at ambient temperature. Concentration and purification by flash column chromatography (0-80% hexane (1% DEA)/ethyl acetate) to give the product.
Cyclization and salt formation of N- (3- ((cyclohexylmethyl) (3- ((4- (dimethylamino) phenyl) sulfonamido) propyl) amino) propyl) piperidine-1-sulfonamide is carried out in a similar manner as pathway 8 to give 4-((9- (cyclohexylmethyl) -13- (piperidin-1-ylsulfonyl) -5,9, 13-triazaspiro [ 2.11)]Tetradecan-5-yl) sulfonyl) -N, N-dimethylaniline hydrochloride (compound a 19). C of MS (EI)31H53N5O4S2Found value of 624[ M + H]+。
The following compounds were synthesized in a similar manner: the cyclisation of compounds a25, a26, a27, a28 and a29 was carried out using NMP as solvent.
To a solution of the amine (67mg,0.14mmol) in DCM (12mL) was added DIEA (35mg,0.27mmol) and then 4-chlorobenzoyl chloride (24mg,0.14 mmol). After standing at ambient temperature for 30 min, the reaction was quenched with sodium bicarbonate (saturated), extracted with DCM (3 ×), dried over sodium sulfate, and filtered. Flash column chromatography (0-60% hexane (1% DEA)/ethyl acetate) afforded (5, 13-bis (piperidin-1-ylsulfonyl) -5,9, 13-triazaspiro [2.11 ]]Tetradecan-9-yl) (4-chlorophenyl) methanone (compound A24). C of MS (EI)28H44ClN5O5S2Measured value 630[ M + H]+。
Pathway 11
To a solution of N, N-3-trimethylaniline (1.35g,10.0mmol) in CHCl3Chlorosulfonic acid (4mL) was added to the solution (4 mL). The reaction mixture was heated at 80 ℃ for 18 hours. The mixture was cooled to ambient temperature and applied with DCM (20mL) dilution. The resulting mixture was poured into ice water (30mL), followed by saturated Na2CO3Adjusting the pH value of the aqueous solution to 7-8. The organic layer was separated and washed with saturated NaHCO3Washing with aqueous solution, and passing through anhydrous Na2SO4Dried and concentrated. The residue was recrystallized from petroleum ether/EtOAc (10:1,10mL) to give 4- (dimethylamino) -2-toluenesulfonyl chloride.1H NMR(400MHz,CDCl3):δ7.88(d,J=9.6Hz,1H),6.53(m,2H),3.09(s,6H),2.70(s,3H)。
Preparation of 4- { [9- (cyclohexylmethyl) -13- (piperidine-1-sulfonyl) -5,9, 13-triazaspiro [2.11 ] following the procedure described in route 12]Tetradecan-5-yl]Sulfonyl } -N, 3-trimethylaniline to give compound a 30.1H NMR(400MHz,DMSO-d6) δ 9.57(br s,1H),7.50(d, J ═ 8.8Hz,2H),6.85(m,2H),3.95(br s,1H),2.89 to 3.55(m,24H),1.45 to 1.90(m,15H),1.28(m,4H),0.95(m,2H),0.66(br s, 4H). C of MS (EI)32H55N5O4S2Found 638[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 12
To a solution of piperidine-1-sulfonyl chloride (68.3g,0.37mol) in toluene (350mL) was added dropwise a solution of propane-1, 3-diamine (83.4g,1.12mol) in toluene (150 mL). The reaction mixture was stirred at ambient temperature overnight. The resulting slurry was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH ═ 50:1 to 20:1) to give N- (3-aminopropyl) piperidine-1-sulfonamide.1HNMR(400MHz,CDCl3):δ3.17(m,6H),2.88(t,J=6.0Hz,2H),1.65(m,6H),1.54(m,2H)。
N- (3-aminopropyl) piperidine-1-sulfonamide (22.62mmol) in toluene (90.0mL) was reacted with the ringThe hexane carboxaldehyde (2.8g,24.89mmol) mixture was heated at reflux overnight and water was removed by dean stark apparatus. The mixture was cooled to ambient temperature and concentrated in vacuo. The resulting product was dissolved in ethanol (35mL) and NaBH added4(1.66g,43.7 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with 2N aqueous HCl (30mL) and then adjusted to pH 10 with aqueous NaOH. The resulting mixture was extracted with ethyl acetate (50mL) and the organic layer was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH ═ 50:1 to 40:1) to give N- (3- (cyclohexylmethylamino) propyl) piperidine-1-sulfonamide.1HNMR(400MHz,CDCl3) δ 3.17(m,6H),2.78(t, J ═ 6.0Hz,2H),2.45(d, J ═ 6.4Hz,2H),1.75(m,12H),1.44(m,1H),1.23(m,3H),0.96(m, 2H). C of MS (EI)15H31N3O2S found value 318[ M + H [)]+。
To N- (3- (cyclohexylmethylamino) propyl) piperidine-1-sulfonamide (2.8g,8.83mmol) in CH3CN (50mL) added Na2CO3(0.97g,9.19mmol), LiI (0.28g,2.12mmol) and 3-bromopropylphthalimide (5.66g,21.19 mmol). The reaction mixture was heated at reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:3) to give N- (3- ((cyclohexylmethyl) (3- (1, 3-bisoxoisoindolin-2-yl) propyl) amino) propyl) piperidine-1-sulfonamide.1H NMR(400MHz,CDCl3):δ7.85(m,2H),7.73(m,2H),5.82(br s,1H),3.68(t,J=7.2Hz,2H),3.17(m,6H),2.46(m,4H),2.14(m,2H),1.82(m,2H),1.67(m 12H),1.45(m,3H),1.18(m,2H),0.87(m,2H)。
To a solution of N- (3- ((cyclohexylmethyl) (3- (1, 3-bisoxoisoindolin-2-yl) propyl) amino) propyl) piperidine-1-sulfonamide (500mg,0.10mmol) in EtOH (5mL) was added NH2NH2(1.5mL,2.55 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (20 mL). The resulting mixture was washed with water (2X 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propaneYl) piperidine-1-sulfonamide (380mg, quantitative).1HNMR(400MHz,CDCl3) δ 3.17(m,6H),2.78(t, J ═ 6.8Hz,2H),2.45(m,4H),2.14(d, J ═ 7.2Hz,2H),1.82(m,2H),1.67(m 12H),1.45(m,3H),1.18(m,2H),0.87(m, 2H). C of MS (EI)18H38N4O2S found 375[ M + H [ ]]+。
To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) piperidine-1-sulfonamide (2.42g,6.49mmol) and DIEA (1.31g,10.3mmol) in DCM (50mL) was added sulfonyl chloride (1.69g,7.13 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was washed with water (50 mL). The organic layer was passed over anhydrous Na2SO4Dried and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM ═ 1:80 to 1:30) to give N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) -2-fluorophenylsulfonylamino) propyl) amino) propyl) piperidine-1-sulfonamide.1H NMR(400MHz,CDCl3) δ 7.66(m,1H),6.43(m,2H),5.58(br s,2H),3.15(m,6H),3.03(s,6H),2.99(br s,2H)2.46(br s,4H),2.12(br s,2H), 1.30-1.70 (m,18H),1.21(m,4H),0.82(m, 2H). C of MS (EI)26H46FN5O4S2Measured value 575[ M + H [ ]]+。
To a solution of N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) -2-fluorophenylsulfonylamino) propyl) amino) propyl) piperidine-1-sulfonamide (2.28g,3.97mmol) in DMF (20mL) was added sodium hydride (400mg,3.97 mmol). The mixture was stirred at ambient temperature for 30 minutes. Cyclopropane-1, 1-diylbis (methylene) diethylsulfonate (1.3g,3.97mmol) was added and the reaction mixture was stirred at 80 ℃ for 2 hours. The mixture was cooled to ambient temperature and poured into water (150 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (50mL × 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:15 to 1:8) to give the free base and was dissolved in ether (5 mL). Hydrochloric acid (1.5mL or 3N in 1, 4-dioxane) was added and the mixture was stirred for 0.5 h. The solvent was removed under vacuum and the residue wet-milled 3 times with diethyl ether to give compound a 40.1H NMR(400MHz,DMSO-d6):δ9.89(br s,1H),7.54(m,1H),6.63(m,2H),3.67(br s,1H),3.55-2.89(m,23H),1.90-1.45(m,15H),1.28(m,4H),0.95(m,2H),0.69(m, 4H). C of MS (EI)31H52FN5O4S2Found value of 643[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 13
To trifluorosulfonic acid 1- ((1H-imidazol-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (1.69g,4.65mmol, ref: J.Org.chem.2002,68,115-119.) and 4-phenylpiperidine (750mg,4.65mmol) was added ACN (16mL) and the solution was allowed to stand for 2 hours. Followed by direct flash column chromatography (0-80% hexane/ethyl acetate) concentration and purification to give the product.
To a solution of 1- ((1H-imidazol-1-yl) sulfonyl) -4-phenylpiperidine (600mg,2.06mmol) in DCM at 0 ℃ was added methyl trifluoromethanesulfonate (0.23mL,2.06mmol) over 5 minutes. After allowing to stand for 30 minutes, the mixture was concentrated to give 3-methyl-1- ((4-phenylpiperidin-1-yl) sulfonyl) -1H-imidazol-3-ium trifluoromethanesulfonate, which was used further without further purification. C of MS (EI)15H20N3O2S found value 307[ M]+。
The following compounds were synthesized in a similar manner:
trifluoromethanesulfonic acid 1- ((8-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A51).
Trifluoromethanesulfonic acid 1- ((7-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A52).
Trifluoromethanesulfonic acid 1- ((6-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A53).
Trifluoromethanesulfonic acid 1- ((5-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A54).
Trifluoromethanesulfonic acid 1- ((6-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A59).
Trifluoromethanesulfonic acid 1- ((6-bromo-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 60).
Trifluoromethanesulfonic acid 1- ((4-isopropoxypiperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester hydrochloride (intermediate of compound a 66).
Trifluoromethanesulfonic acid 1- ((4- (cyclopent-1-en-1-yl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 67).
Trifluoromethanesulfonic acid 1- ((4- (cyclohex-1-en-1-yl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 68).
Trifluoromethanesulfonic acid 1- ((4- (3-chlorophenyl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A69).
Trifluoromethanesulfonic acid 1- ((4- (2-chlorophenyl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A73).
Trifluoromethanesulfonic acid 1- ((4- (4-chlorophenyl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A74).
Trifluoromethanesulfonic acid 1- ((4- (1H-pyrazol-1-yl) piperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 79).
Trifluoromethanesulfonic acid 1- ((4- (benzo [ d ] oxazol-2-yl) piperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A80).
Trifluoromethanesulfonic acid 3-methyl-1- ((4- (pyrimidin-2-yl) piperidin-1-yl) sulfonyl) -1H-imidazol-3-ium ester (intermediate of compound a 81).
Trifluoromethanesulfonic acid 1- ((2-chloro-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of Compound A82).
Trifluoromethanesulfonic acid 1- ((5-chloroisoindolin-2-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 89).
Pathway 14
To a solution of 4- ((9- (cyclohexylmethyl) -3-methylene-1, 5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline (97mg,0.21mmol) in ACN (0.8mL) was added trifluoromethanesulfonic acid 3-methyl-1- ((4-phenylpiperidin-1-yl) sulfonyl) -1H-imidazol-3-ium ester (95mg,0.21mmol) and the mixture was heated to 80 ℃ for 8 hours, followed by direct concentration and purification with flash column chromatography (0-70% hexane (1% DEA)/ethyl acetate) to give the free base. To this free base were added diethyl ether (5mL) and HCl (52. mu.L of 4N HCl in 1, 4-dioxane) and the mixture was allowed to stand for 10 minutes and then concentrated to give 4- { [9- (cyclohexylmethyl) -3-methylene-5- [ (4-phenylpiperidin-1-yl) sulfonyl group]-1,5, 9-triazacyclododeca-1-yl]Sulfonyl } -N, N-dimethylaniline hydrochloride (compound a 35). C of MS (EI)36H55N5O4S2Found value 686[ M + H]+。
The following compounds were synthesized in a similar manner:
To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4- (dimethylamino) benzenesulfonamide (838mg,1.84mmol) in ACN (5mL) was added trifluoromethanesulfonic acid 3-methyl-1- ((4-phenylpiperidin-1-yl) sulfonyl) -1H-imidazol-3-ium ester (838mg,1.84mmol) and the mixture was heated to 80 ℃ for 8 hours, which was directly concentrated and purified with flash column chromatography (0-70% hexane (1% DEA/ethyl acetate) to give the product.1HNMR(400MHz,CDCl3):δ7.68(d,J=8.8Hz,2H),7.33(m,5H),6.68(d,J=8.8Hz,2H),5.75(br s,2H),3.84(m,2H),3.18(m,2H),3.05(s,6H),2.91(m,4H),2.65(m,1H),2.43(m,4H),2.08(m,2H),1.73(m,12H),1.40(m,1H),1.15(m,4H),0.85(m,2H)。
To a solution of 4- ((9- (cyclohexylmethyl) -3-methyl-5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline (123mg,0.194mmol) in NMP (10mL) was added sodium hydride (19mg of a 60% dispersion in mineral oil, 0.485mmol) over 20 minutes. The mixture was stirred at ambient temperature for 30 minutes and then at 80 ℃ for an additional 20 minutes. The bis-sulfonate was then added over a1 hour time course. After 8 hours at 80 ℃, the mixture was cooled to ambient temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3 ×), the combined organics were washed with brine (3 ×), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-50% hexane (1% DEA)/ethyl acetate) afforded the free base. The free base was converted to the HCl salt by the addition of diethyl ether (5mL) and HCl (4N dioxane solution, 50 uL). Concentrated for 10 min to give 4- { [9- (cyclohexylmethyl) -3-methyl-5- [ (4-phenylpiperidin-1-yl) sulfonyl group]-1,5, 9-triazacyclododeca-1-yl]Sulfonyl } -N, N-dimethylaniline hydrochloride (compound a 44). C of MS (EI)36H57N5O4S2Found value of 688[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 16
To a solution of 1, 1-bis (hydroxymethyl) cyclopropane (5.00,49.0mmol) in acetone (20mL) was added TEA (2.2eq,108mmol) and the mixture was cooled to 0-5 ℃. Ethanesulfonyl chloride was added at a rate to maintain the internal temperature below 10 deg.C (-1 hour). After stirring at ambient temperature for an additional 2 hours, the mixture was diluted with 150mL of water, extracted with ethyl acetate (2 × 50mL), washed with brine, dried over sodium sulfate, filtered, and concentrated to give the product.1HNMR(400MHz,CDCl3) δ 4.16(s,4H),3.20(m,4H),1.46(t, J ═ 7.2Hz,6H),0.83(s, 4H). C of MS (EI)9H18O6S2Found 287[ M + H]+。
The following compounds were synthesized in a similar manner: diethylsulfonic acid 2-methylpropane-1, 3-diyl ester (intermediate of Compound A44).
Pathway 17
To a solution of N- (3- ((cyclohexylmethyl) (3- ((4- (dimethylamino) phenyl) sulfonamido) propyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide (89mg,0.14mmol) in NMP (7mL) was added NaH (14mg of a 60% dispersion in mineral oil, 0.35mmol) portionwise over 20 minutes. The mixture was stirred at ambient temperature for 30 minutes and then at 80 ℃ for 20 minutes. The dichloride was then added and the mixture was heated at 80 ℃. After 8 hours at 80 ℃, the mixture was cooled to ambient temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3 ×), the combined organics were washed with brine (3 ×), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-50% hexane (1% DEA)/ethyl acetate) afforded the product. Ether (5mL) and HCl (4N dioxane) were addedLiquid, 35uL) the product was converted to the HCl salt. The mixture was concentrated to give 4- { [5- (cyclohexylmethyl) -9- [ (4-phenylpiperidin-1-yl) sulfonyl ] sulfonyl]-1,5, 9-triazacyclotridecan-1-yl group]Sulfonyl } -N, N-dimethylaniline hydrochloride (compound B5). C of MS (EI)36H57N5O4S2Found value of 688[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 18
N- (4- ((3-aminopropyl) (cyclohexylmethyl) amino) but-2-yl) -4- (dimethylamino) benzenesulfonamide was synthesized according to pathway 2 using the appropriate sulfonyl chloride.
4- ((5- (cyclohexylmethyl) -2-methyl-11-methylene-9- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline was synthesized following the procedure described in route 15 using 3-chloro-2- (chloromethyl) prop-1-ene to give 4- ((5- (cyclohexylmethyl) -2-methyl-11-methylene-9- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, n-dimethylaniline (Compound B6). C of MS (EI)37H57N5O4S2Found 700[ M + H]+。
The following compounds were synthesized in a similar manner:
pathway 19
To a solution of N- (3- ((cyclohexylmethyl) (3- ((4- (dimethylamino) phenyl) sulfonamido) propyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide (33mg,0.052mmol) in NMP (3mL) was added sodium hydride (4.6mg of a 60% dispersion in mineral oil, 0.11 mmol). The mixture was stirred at ambient temperature for 30 minutes and then at 80 ℃ for an additional 20 minutes. Then dichloride (19mg,0.052mmol) was added. After 2 hours at 80 ℃, the mixture was cooled to ambient temperature, diluted with brine and ethyl acetate, extracted with ethyl acetate (3 ×), the combined organics were washed with brine (3 ×), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-50% hexane (1% DEA)/ethyl acetate) afforded 9- (cyclohexylmethyl) -1- [4- (dimethylamino) benzenesulfonyl]-5- [ (4-phenylpiperidin-1-yl) sulfonyl]1,5, 9-triazacyclododeca-3-ol (compound A55). C of MS (EI)35H55N5O5S2Measured value 690[ M + H]+。
To a solution of 3-fluoro-4-iodoaniline (1.11g,4.68mmol) in acetonitrile (15.00mL) was added 37% aqueous formaldehyde (8.0mL,99.9mmol) and sodium cyanoborohydride (1.88g,29.97 mmol). Acetic acid (1mL) was then added dropwise over 10 minutes and the reaction mixture was stirred at ambient temperature overnight. NaOH (1N,30mL) was added and the resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-fluoro-4-iodo-N, N-dimethylaniline.1H NMR(400MHz,CDCl3):δ7.47(m,1H),6.43(m,1H),6.28(m,1H),2.94(s,6H)。
To a solution of 3-fluoro-4-iodo-N, N-dimethylaniline (500mg,1.89mmol) in diethyl ether (5mL) at-78 deg.C was added N-BuLi (0.8mL,1.89 mmol). The mixture was stirred at this temperature for 0.5 h. Sulfuryl dichloride (405mg,3mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched with water (10mL) followed by saturated NaHCO3The aqueous solution was adjusted to pH 8. The resulting mixture was extracted with ethyl acetate (10 mL). The organic layer was separated, dried and concentrated. The residue was purified by silica gel column chromatography to give 4- (dimethylamino) -2-fluorobenzene-1-sulfonyl chloride.1H NMR(400MHz,CDCl3):δ7.73(m,1H),6.43(m,2H),3.15(s,3H)。
Pathway 21
To a solution of 9- (cyclohexylmethyl) -1- ((4- (dimethylamino) phenyl) sulfonyl) -5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododecan-3-ol (30mg,0.043mmol) in toluene (0.5mL) was added NaH (1.6mg of a 60% dispersion in mineral oil, 0.065mmol) and subsequently iodomethane (14 μ L,0.22 mmol). After stirring for 1 hour, the mixture was quenched with water, extracted with DCM (2 ×), the organics were combined and dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-50% hexane/ethyl acetate + 1% DEA) afforded 4- { [9- (cyclohexylmethyl) -3-methoxy-5- [ (4-phenylpiperidin-1-yl) sulfonyl]-1,5, 9-triazacyclododeca-1-yl]Sulfonyl } -N, N-dimethylaniline (Compound A)61). C of MS (EI)36H57N5O5S2Measured value 704[ M + H]+。
Pathway 22
To 9- (cyclohexylmethyl) -1- ((4- (dimethylamino) phenyl) sulfonyl) -5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododeca-3-ol (171mg,0.248mmol) was added DCM (10mL) and subsequently busulfan (126mg,0.297 mmol). The mixture was allowed to stand at room temperature for 2 hours, then it was directly concentrated with FCC (0-60% hexane (1% DEA)/ethyl acetate) and purified to give 9- (cyclohexylmethyl) -1- ((4- (dimethylamino) phenyl) sulfonyl) -5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododeca-3-one (compound B20). C of MS (EI)35H53N5O5S2Found value of 688[ M + H]+。
Pathway 23
To a solution of 4- ((5- ((6-bromo-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -9- (cyclohexylmethyl) -3-methylene-1, 5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline (70mg,0.095mmol) in DMF (0.7mL) was added water (0.1mL), phenylboronic acid (13mg,0.10mmol), Pd (dppf) Cl2DCM (7.8mg,0.001mmol) and sodium carbonate (30mg,0.29 mmol). The mixture was heated to 80 ℃ for 1 hour, then diluted with brine, extracted with ethyl acetate (2 ×), dried over sodium sulfate, filtered, and concentrated. Flash column chromatography (0-50% hexane (1% DEA)/ethyl acetate) was used to give 4- ((9- (cyclohexylmethyl) -3-methylene-5- ((6-phenyl-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -1,5, 9-triazacyclododec-1-yl) sulfonyl) -N, N-dimethylaniline (Compound A63). C of MS (EI)40H53N5O4S2Measured value 734[ M + H]+。
Pathway 24
Cyclopentanone (5.50g,65.5mmol) and Na in DCM (130mL) at-20 deg.C2CO3(10.4g,98.2mmol) mixture Tf was added2O (18.6g,72.0 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solids were filtered off and the filtrate was concentrated to give cyclopentenyl trifluoromethanesulfonate.
A solution of cyclopentenyl trifluoromethanesulfonate (7.7g,35.6mmol) in 1, 4-dioxane (105mL) and water (50mL) was degassed and then filled with argon. To this solution were added tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3-dioxolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (6.0g,19.4mmol), Pd (PPh)3)4(1.02g,0.88mmol) and sodium carbonate (10.3g,97.1 mmol). The reaction mixture was stirred at 90 ℃ overnight and then cooled to ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, over anhydrous Na2SO4Dried and concentrated under reduced pressure. Flash column chromatography (etoac/hexanes ═ 1:99 to 5:95) to give 4-cyclopentenyl-5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester.1HNMR(400MHz,CDCl3):δ5.73(br s,1H),5.56(br s,1H),4.00(br s,2H),3.45(br s,2H),2.47(m,4H),2.33(br s,2H),1.94(m,2H),1.48(s,9H)。
To a solution of 4-cyclopentenyl-5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.3g,15.3mmol) in methanol (30mL) was added Pd/C (0.6 g). The mixture was hydrogenated at 15psi for 5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-cyclopentylpiperidine-1-carboxylic acid tert-butyl ester.
To a solution of tert-butyl 4-cyclopentylpiperidine-1-carboxylate (2.9g,11.5mmol) in ethyl acetate (15mL) was added EtOAc/HCl (4N,20 mL). The mixture was stirred for 2 hours and the solvent was removed. The resulting product was washed with diethyl ether to give 4-cyclopentylpiperidine hydrochloride.1H NMR(400MHz,D2O):δ3.25(m,2H),2.75(m,2H),1.84(m,2H),1.61(m,2H),1.45(m,8H),0.96(m,2H)。
4-Cyclopentylpiperidine hydrochloride trifluoromethanesulfonate (1.4g,9.5mmol) and 1- (1H-imidazol-1-ylsulfonyl) -3-methyl-1H-imidazol-3-ium ester (3.45g,9.5mmol) were mixed in CH3CN (20 mL). The mixture was stirred at ambient temperature overnight. The solution was removed. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:9 to 1:3) to give 1- (1H-imidazol-1-ylsulfonyl) -4-cyclopentylpiperidine.1HNMR(400MHz,CDCl3):δ7.91(s,1H),7.24(s,1H),7.14(s,1H),3.87(m,2H),2.51(m,2H),1.83(m,4H),1.54(m,5H),1.33(m,2H),1.08(m,3H)。
To a solution of 1- (1H-imidazol-1-ylsulfonyl) -4-cyclopentylpiperidine (500mg,1.8mmol) in DCM (5mL) was added MeOTf (0.3g,1.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed and the resulting product was washed with diethyl ether to give 1- ((4-cyclopentylpiperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate.1H NMR(400MHz,CD3OD):δ9.59(s,1H),8.02(s,1H),7.78(s,1H),4.00(s,3H),3.95(m,2H),2.87(m,2H),1.81(m,4H),1.54(m,6H),1.23(m,4H)。
The following compounds were synthesized in a similar manner:
trifluoromethanesulfonic acid 1- ((4-cyclohexylpiperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 65).
Trifluoromethanesulfonic acid 3-methyl-1- ((4- (tetrahydro-2H-pyran-4-yl) piperidin-1-yl) sulfonyl) -1H-imidazol-3-ium ester (intermediate of compound a 78).
Pathway 25
To 9- (cyclohexylmethyl) -1- ((4- (dimethylamino) phenyl) sulfonyl) -5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododeca-3-one (19mg,0.028mmol) in DCM (0.5mL) and methanol (0.05mL) was added hydroxylamine hydrochloride (5.8mg,0.083mmol) and sodium acetate (6.8mg,0.083 mmol). The mixture was stirred at ambient temperature for 6 hours, followed by rapid stirringColumn chromatography (0-60% hexane (1% DEA)/ethyl acetate) was concentrated and purified to give 9- (cyclohexylmethyl) -1- ((4- (dimethylamino) phenyl) sulfonyl) -5- ((4-phenylpiperidin-1-yl) sulfonyl) -1,5, 9-triazacyclododeca-3-one oxime (compound a 75). C of MS (EI)35H54N6O5S2Measured value 703[ M + H]+。
Pathway 26
A solution of 1-chloro-2-iodobenzene (5.0g,21.1mmol) in DMF (150mL) was degassed and then filled with argon. To this was added tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3-dioxolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (7.13g,23.0mmol), Pd (dppf) Cl2(1.7g,2.1mmol) and potassium carbonate (8.69g,63.0 mmol). The reaction mixture was stirred at 110 ℃ overnight and then cooled to ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, over anhydrous Na2SO4Dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (etoac/hexanes ═ 1:9 to 1:4) afforded 4- (2-chlorophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester.1H NMR(400MHz,CDCl3):δ7.37(m,1H),7.18(m,3H),5.67(m,1H),4.06(m,2H),3.64(m,2H),2.46(br s,2H),1.51(s,9H)。
To a solution of 4- (2-chlorophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.0g,6.8mmol) in MeOH (20mL) was added HCl/MeOH (3M,20 mL). The mixture was stirred at ambient temperature for 2 hours. The resulting solution of 4- (2-chlorophenyl) -1,2,3, 6-tetrahydropyridine hydrochloride was used directly in the next step.
To a solution of 4- (2-chlorophenyl) piperidine hydrochloride in MeOH/HCl was added PtO2(0.1 g). The mixture was hydrogenated at 15psi for 3 hours. The catalyst was filtered off and the filtrate was concentrated to give the product.1HNMR(400MHz,DMSO-d6):δ9.19(br s,2H),7.37(m,1H),7.36(m,4H),3.44(m,1H),3.33(m,2H),3.08(m,2H),1.95(m,4H)。
The free base (0.95g,4.8mmol) and trifluoro were combinedMethanesulfonic acid 1- (1H-imidazol-1-ylsulfonyl) -3-methyl-1H-imidazol-3-ium ester (1.76g,4.8mmol) was mixed with CH3CN (10 mL). The mixture was stirred at ambient temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography to give 1- (1H-imidazol-1-ylsulfonyl) -4- (2-chlorophenyl) piperidine.1H NMR(400MHz,CDCl3):δ8.01(s,1H),7.36(m,2H),7.18(m,4H),4.07(m,2H),3.06(m,1H),2.74(m,2H),1.99(m,2H),1.81(m,2H)。
To a solution of 1- (1H-imidazol-1-ylsulfonyl) -4- (2-chlorophenyl) piperidine (501mg,1.5mmol) in DCM (5mL) was added MeOTf (0.27g,1.63 mmol). The mixture was stirred at ambient temperature overnight. The solution was removed. The resulting product was washed with diethyl ether to give 1- ((4- (2-chlorophenyl) piperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (intermediate of compound a 57).1HNMR(400MHz,CD3OD):δ9.65(s,1H),8.08(s,1H),7.82(s,1H),7.39(m,4H),4.16(m,2H),4.02(s,3H),3.31(m,3H),2.03(m,2H),1.85(m,2H)。
The following compounds were synthesized in a similar manner:
trifluoromethanesulfonic acid 1- ((4- (3-chlorophenyl) piperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 58).
Trifluoromethanesulfonic acid 1- ((4- (4-chlorophenyl) piperidin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (intermediate of compound a 72).
Pathway 27
Ethyl chloroformate (107g,1.14mol) was added dropwise at 0 deg.C to 2- (3-chlorophenyl) ethylamine (149g,0.95mol) and TEA (144g,1.42mol) in DCM (1.5L). The reaction mixture was stirred for 3 hours and then with 1N HCl aqueous solution (1L) and saturated NaHCO3Aqueous (600mL) wash. The DCM layer was dried over anhydrous sodium sulfate and concentrated to give methyl 3-chlorophenethylcarbamate.1H NMR(400MHz,CDCl3):δ7.27(m,3H),7.08(m,1H),4.77(m,1H),3.78(s,3H),3.44(m,2H),2.80(m,2H)。
Methyl 3-Chlorobenzoethylcarbamate (193g,0.9mol) was dissolved in CF3SO3H (1.36 kg). The mixture was heated overnight at 120 ℃. The mixture was cooled to ambient temperature and poured into ice water (4L). The resulting product was collected by filtration and washed with diethyl ether to give 6-chloro-3, 4-dihydroisoquinolin-1 (2H) -one.1H NMR(400MHz,CDCl3):δ8.01(m,1H),7.35(m,1H),7.25(m,2H),6.21(br s,1H),3.60(m,2H),3.01(m,2H)。
To a solution of 6-chloro-3, 4-dihydroisoquinolin-1 (2H) -one (33g,182mmol) in THF (330mL) was added BH dropwise3-Me2S (73mL,729 mmol). The reaction mixture was refluxed overnight. The mixture was cooled to ambient temperature and then quenched with 6n hcl aqueous solution (300 mL). THF was removed under reduced pressure and the remaining solution was refluxed overnight. The mixture was concentrated to volume and then basified with 2n naoh aqueous solution. The resulting mixture was extracted with DCM. The DCM layer was dried over anhydrous sodium sulfate and concentrated to give 6-chloro-1, 2,3, 4-tetrahydroisoquinoline.
To 6-chloro-1, 2,3, 4-tetrahydroisoquinoline (18.5g,0.11mol) in CH3CN (180mL) solution was added the compound trifluoromethanesulfonic acid 2, 3-dimethyl-1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) -1H-imidazol-3-ium ester (43.5g,0.11mol, ref: J.Org.Chem.2002,68, 115-. The reaction mixture was stirred overnight at 30 ℃. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:1) to give 6-chloro-2- (2-methyl-1H-imidazol-1-ylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline.1HNMR(400MHz,CDCl3):δ7.21(m,1H),7.18(s,1H),7.02(m,1H),6.94(m,1H),4.45(s,2H),3.62(m,2H),2.92(m,2H),2.67(s,3H)。
To 6-chloro-2- (2-methyl-1H-imidazole-1-ylsulfonyl) -1,2,3, 4-tetrahydroisoquinoline (25.5g,82mmol) in DCM (260mL) was added CF3SO3Me (13.45g,82 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed and the residue was washed with diethyl ether to give trifluoromethanesulfonic acid 1- (6-chloro-3, 4-dihydroisoquinolin-2 (1H) -ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester.
To trifluoromethane sulfonic acid1- (6-chloro-3, 4-dihydroisoquinolin-2 (1H) -ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester (8.7g,18.4mmol) in CH3CN (100mL) solution was added (R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (5.0g,18.4 mmol). The reaction mixture was stirred overnight at 30 ℃. The solvent was removed, and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:3 to 1:1) to give (S) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (compound B10).1H NMR(400MHz,CDCl3):δ7.85(m,2H),7.43(m,2H),7.18(m,2H),7.03(m,1H),4.35(s,2H),3.48(m,2H),3.18(s,6H),3.15(m,1H),2.95(m,6H),2.85(m,1H),1.89(m,1H),0.89(m,3H)。
(S) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (300mg,0.6mmol) was dissolved in NMP (3mL) and NaH (60%, 96mg,2.4mmol) was added. The mixture was stirred at ambient temperature for 30 minutes and then heated at 80 ℃ for 20 minutes. The mixture was cooled to ambient temperature. A solution of bis (propane-3, 1-diyl) bis ((cyclohexylmethyl) azanediyl) sulfonate (231mg,0.6mmol) in NMP (1mL) was added. The reaction mixture was heated at 80 ℃ for 1 hour, then cooled to ambient temperature and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (15 mL). The extract was washed with brine and concentrated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:8 to 1:3) to give compound a 87. C of MS (EI)34H52ClN5O4S2Found 695[ M + H]+。1HNMR(400MHz,CDCl3):δ7.59(d,J=8.8Hz,2H),7.15(m,2H),7.00(m,1H),6.68(d,J=8.8Hz,2H),4.34(m,2H),3.71(m,2H),3.45(m,2H),3.17(m,3H),3.05(s,6H),2.88(m,4H),2.25(m,2H),2.15(m,6H),1.95(m,2H),1.65(m,8H),1.23(m,6H),0.95(m,5H)。
The following compounds were synthesized in a similar manner:
pathway 28
To benzylamine (37.7g,0.350mol) CH3CN (1L) solution was added with 3-chloropropan-1-ol (100g,1.06mol) and Na2CO3(131g,1.24 mol). The reaction mixture was refluxed for 50 hours, then cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM ═ 1:99 to 3:97) to give 3,3' - (benzylazalidyl) diprop-1-ol.1H NMR(400MHz,CDCl3):δ7.34(m,5H),3.70(m,4H),3.61(s,2H),3.48(s,2H),2.68(m,4H),1.78(m,4H)。
To a solution of 3,3' - (benzylazalidyl) diprop-1-ol (55g) in MeOH (500mL) was added Pd/C (10 g). The mixture was hydrogenated at 15kg pressure for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated to give 3,3' -azaalkanediyl diprop-1-ol.1HNMR(400MHz,CDCl3):δ3.78(m,4H),3.46(s,2H),2.84(m,4H),1.75(m,4H)。
To a solution of 3,3' -azanediyldipropan-1-ol (15g,113mmol) in DCM (300mL) were added cyclohexanecarboxaldehyde (18.8g,141mmol) and NaBH (OAc)3(72.5g,0.34 mol). The mixture was stirred for 0.5 h and HOAc (20.4g,0.34mol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was quenched with water (150mL) and then adjusted to pH 12 with NaOH. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM ═ 3:97 to 1:9) to give 3,3' - ((cyclohexylmethyl) azanediyl) bis (propan-1-ol).1H NMR(400MHz,CDCl3):δ3.75(m,4H),2.64(m,4H),2.18(m,2H),1.75(m,9H),1.55(m,1H),1.21(m,3H),0.89(m,1H)。
To a solution of compound 3,3' - ((cyclohexylmethyl) azanediyl) bis (propan-1-ol) (1.2g,5.2mmol) and TEA (1.0g,10.4mmol) in DCM (15mL) was added MsCl (1.18g,10.4mmol) at 0 ℃. The reaction mixture was stirred for 4 hours and then quenched with water (15 mL). The DCM layer was separated, dried over anhydrous sodium sulfate and concentrated to give the compound dimethyl sulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (propane-3, 1-diyl) ester. The disulfonate was used immediately without further purification.
Pathway 29
Boc was added to a solution of propane-1, 3-diamine (100g,1.35mol) in THF (800mL) at 0-10 deg.C2O (73.6g,0.34mol) in THF (200 mL). The reaction mixture was stirred and water (1L) was added. The resulting mixture was extracted with ethyl acetate (500mLx 2). The organic layers were combined and concentrated to a volume of 400 mL. Hexane (300mL) was added and to the resulting solution was added 15% aqueous oxalic acid (1L). The mixture was stirred for 0.5 hour. The organic layer was decanted and the aqueous layer was adjusted to pH 10 with 3N aqueous NaOH. The resulting mixture was extracted with DCM (600 mL. times.2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 3-aminopropyl carbamic acid tert-butyl ester.1H NMR(400MHz,CDCl3):δ5.03(br s,1H),3.23(br s,2H),2.69(m,2H),1.71(m,2H),1.44(s,9H)。
Triethylamine (4.70g,46.5mmol) was added dropwise to benzyl 3-bromopropylcarbamate (4.2g,15.5mmol) at ambient temperature and the mixture stirred to give a solution of tert-butyl 3-aminopropylcarbamate (2.7g,15.5mmol) in DMF (50 mL). The reaction mixture was heated at 70 ℃ for 1 hour. Most of the DMF was removed under vacuum and the remaining mixture was diluted with water (120mL) and washed with diethyl ether (150mL × 4) to remove most of the dialkylated by-products. The aqueous layer was adjusted to pH 11 with 1N aqueous NaOH and extracted with ether (200 mL). The extract was washed with water (150 mL. times.3) to remove unreacted 3-ammoniaTert-butyl cyclopropylcarbamate, dried over anhydrous sodium sulfate and concentrated to give tert-butyl (3- ((3- (((benzyloxy) carbonyl) amino) propyl) carbamate.1H NMR(400MHz,CDCl3):δ7.36(m,5H),5.60(br s,1H),5.11(m,3H),3.30(m,2H),3.20(m,2H),2.68(m,4H),1.70(m,5H),1.44(s,9H)。
To a solution of tert-butyl (3- ((3- (((benzyloxy) carbonyl) amino) propyl) carbamate (100mg,0.27mmol) in DCM (5mL) was added cyclohexanecarboxaldehyde (31mg,0.27mmol) and HOAc (30mg,1.1 mmol). The mixture is stirred for 0.5 h and added in one portion to NaBH (OAc)3(235g,1.1 mmol). The reaction mixture was stirred for 4 hours. TLC analysis showed 50% conversion and another portion of cyclohexanecarboxaldehyde (15mg,0.13mmol) was added. The reaction mixture was stirred at ambient temperature overnight. Water (10mL) was added to quench the reaction and HOAc was added to adjust the mixture to pH 2. The mixture was stirred for a further 0.5 h and then adjusted to pH 12 with aqueous NaOH (1N). The organic layer was separated and concentrated to give tert-butyl (3- ((3 (((benzyloxy) carbonyl) amino) propyl) (cyclohexylmethyl) amino) propyl) carbamate.1H NMR(400MHz,CDCl3):δ7.27(m,5H),6.12(br s,1H),5.55(br s,1H),5.01(s,3H),3.34(m,2H),3.18(m,2H),3.08(m,2H),2.80(m,4H),1.65(m,9H),1.44(s,9H),1.12(m,6H)。
To a solution of tert-butyl (3- ((3- (((benzyloxy) carbonyl) amino) propyl) (cyclohexylmethyl) amino) propyl) carbamate (0.50g,1.1mmol) in MeOH (5mL) was added Pd/C (0.1 g). The mixture was hydrogenated at 15psi for 3 hours. The mixture was filtered and the filtrate was concentrated to give tert-butyl (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) carbamate.1HNMR(400MHz,CDCl3):δ5.78(br s,1H),3.19(br s,2H),2.78(m,2H),2.40(m,4H),2.13(m,2H),1.98(br s,2H),1.67(m,9H),1.44(s,9H),1.12(m,4H),0.89(m,2H)。
To tert-butyl (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) carbamate (1.2g,3.7mmol) in CH3CN (10mL) solution was added 3-methyl-1- (4-phenylpiperidin-1-ylsulfonyl) -1H-imidazol-3-ium (1.47g,3.7 mmol). The reaction mixture is brought to ambient temperatureStir overnight. The solvent was removed, and the residue was purified by silica gel column chromatography to give tert-butyl 3- ((cyclohexylmethyl) (3- (4-phenylpiperidine-1-sulfonylamino) propyl) amino) propylcarbamate.
To a solution of tert-butyl 3- ((cyclohexylmethyl) (3- (4-phenylpiperidine-1-sulfonylamino) propyl) amino) propylcarbamate (0.85g, 1.5mmol) in DCM (15mL) was added TFA (10 mL). The reaction mixture was stirred at ambient temperature for 3 hours. The solvent was removed and the residue was dissolved in DCM (50 mL). The solution was basified with 1N aqueous NaOH. DCM layer was washed with anhydrous Na2SO4Dried and concentrated to give N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide.
To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide (90mg,0.20mmol) in DCM (5mL) was added TEA (40mg,0.4 mmol). The mixture was cooled to 0 ℃ and a solution of 4- (dimethylamino) -2, 6-difluorobenzene-1-sulfonyl chloride (60mg,0.24mmol) in DCM (1mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with DCM (30mL) and then washed with water (20 mL). The organic layer was passed over anhydrous Na2SO4Dried and concentrated. The residue was purified by silica gel column chromatography to give N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) phenylsulfonylamino) propyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide.
To a solution of N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) phenylsulfonylamino) propyl) amino) propyl) -4-phenylpiperidine-1-sulfonamide (80mg,0.123mmol) in NMP (2mL) was added NaH (12mg,0.29 mmol). The mixture was heated at 80 ℃ for 0.5 h. The mixture was cooled to ambient temperature and a solution of 3-chloro-2- (chloromethyl) prop-1-ene (15mg,0.12mmol) in NMP (0.1mL) was added. The reaction mixture was heated at 80 ℃ for 2 hours. The mixture was cooled to ambient temperature and water (20mL) was added. The resulting mixture was extracted with ethyl acetate (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 10:30 to 20:10) to give compound a 86. C of MS (EI)36H53F2N5O4S2Found 733[ M + H ]]+。1H NMR(400MHz,CDCl3):δ7.31(m,5H),6.18(m,2H),5.25(m,2H),4.05(s,2H),3.87(m,4H),3.20(m,4H),3.05(s,6H),2.88(m,2H),2.41(m,4H),2.05(m,5H),1.75(m,9H),1.27(m,6H),0.85(m,2H)。
To a solution of 3, 5-difluoro-4-iodo-N, N-dimethylaniline (500mg,1.77mmol) in diethyl ether (5mL) at-78 deg.C was added N-BuLi (0.71mL,1.77mmol) dropwise. The mixture was stirred at-78 ℃ for 0.5 h. Sulfuryl dichloride (358mg,1.5mmol) was added. The mixture was quenched with water (10mL) and extracted with ethyl acetate (15 mL). The organic layer was passed over anhydrous Na2SO4Dried and concentrated. The residue was purified by silica gel column chromatography to give the crude product, which was further recrystallized from hexane/EtOAc (10:1) to give 4- (dimethylamino) -2, 6-difluorobenzene-1-sulfonyl chloride.1HNMR(400MHz,CDCl3):δ6.21(s,1H),6.18(s,1H),3.09(s,6H)。
Pathway 31
To 1, 3-dichloropropan-2-one (5.0g,39.5mmol) in H2O (50mL) suspension O-methylhydroxylamine hydrochloride (3.5g,41.5mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The organic layer was separated, diluted with ether and concentrated in vacuo (<30 ℃) to obtain 1, 3-dichloropropan-2-one O-methoxime.1HNMR(400MHz,CDCl3):δ4.33(s,2H),4.27(s,2H),3.94(s,3H)。
Pathway 32
To (S) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonylamino) -2-methylpropyl) -3 at 0 ℃,4-dihydroisoquinoline-2 (1H) -sulfanilamide (100.0mg,0.200mmol) in anhydrous NMP (3mL) add NaH (24.0mg,0.600mmol), stir the mixture at ambient temperature for 20 minutes and during this time it turned from a cloudy mixture to almost transparent. Methyl iodide (27 μ L,0.440mmol) was added and the mixture stirred at ambient temperature for 1 hour and progressed no more than-50% completion, so the reaction was completed after an additional hour at ambient temperature with additional amounts of NaH and methyl iodide. Brine (10mL) and EA (10mL) were added. The aqueous layer was extracted with EA (1x5mL) and the organics were combined, washed with brine (3x10mL), dried over sodium sulfate, filtered and concentrated. FCC (hexane/EA 0-70%) gave compound B12. C of MS (EI)23H33ClN4O4S2Measured value 529[ M + H]+。
Pathway 33
To a solution of methyl methacrylate (300g,3.0mol) in MeOH (1.5L) was added (S) -1-phenylethylamine (363g,3 mol). The reaction mixture was refluxed for 5 days. The mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:9 to 1:1) to give methyl 2-methyl-3- ((S) -1-phenylethylamino) propionate.1HNMR(400MHz,CDCl3):δ7.25(m,5H),3.75(m,1H),3.69(s,3H),2.75(m,3H),1.39(m,1H),1.28(m,3H),1.09(m,3H)。
To a solution of methyl 2-methyl-3- ((S) -1-phenylethylamino) propionate (440g,1.99mol) in acetone (6L) was added TsOH-H2O (378g,1.99 mol). The mixture was stirred at ambient temperature for 1 hour. The precipitated solid was collected by filtration and dried to give a salt (300g) and suspended in acetone (2L) and refluxed for 1 hour. The mixture was cooled to ambient temperature and the resulting precipitate was collected by filtration to give a salt, which was suspended in DCM (2L) and saturated K2CO3In aqueous solution (1.5L). The mixture was stirred for 0.5 hour to dissolve the solid. The DCM layer was separated and washed with anhydrous Na2SO4Drying and concentrating to obtain (R) -2-methyl-3- ((S) -1-Phenylethylamino) propionic acid methyl ester.
To a solution of methyl (R) -2-methyl-3- ((S) -1-phenylethylamino) propionate (140g,0.630mol) in MeOH (1.4L) was added HOAc (30mL) and Pd/C (15 g). The mixture was hydrogenated at 60 ℃ under 20kg pressure. The catalyst was removed by filtration, and the filtrate was concentrated to give methyl (R) -3-amino-2-methylpropionate.1HNMR(400MHz,CDCl3):δ5.09(br,3H),3.72(s,3H),3.05(m,1H),2.93(m,1H),2.75(m,1H),1.23(d,J=7.2Hz,3H)。
Adding TEA (160g,1.58mol) and Boc to a solution of methyl (R) -3-amino-2-methylpropionate (112g,0.63mol) in dichloromethane (1L) at 0-5 deg.C2O (152g,0.69 mol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was washed with brine (1L), 2N aqueous HCl (1L) and saturated NaHCO, respectively3Aqueous (1L) wash. The organic layer was passed over anhydrous Na2SO4Dried and concentrated. The residue was purified by silica gel column chromatography to give methyl (R) -3- (tert-butoxycarbonyl) -2-methylpropionate.1HNMR(400MHz,CDCl3):δ4.94(br s,1H),3.70(s,3H),3.31(m,2H),2.70(m,1H),1.52(s,9H),1.18(d,J=7.2Hz,3H)。
To a solution of methyl (R) -3- (tert-butoxycarbonyl) -2-methylpropionate (6g,51.3mmol) in THF (60mL) was added LiBH4(1.12g,102 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was quenched with water (30mL) and then adjusted to pH 2-3 by the addition of 1n aqueous hcl. The resulting mixture was extracted with ethyl acetate and the extract was extracted with saturated NaHCO3Washing with aqueous solution, and passing through anhydrous Na2SO4Dried and concentrated to give (R) -3-hydroxy-2-methylpropylcarbamic acid tert-butyl ester.1H NMR(400MHz,CDCl3):δ3.57(m,1H),3.37(m,2H),3.05(m,1H),1.77(m,1H),1.48(s,9H),0.88(d,J=7.2Hz,3H)。
To a solution of tert-butyl (R) -3-hydroxy-2-methylpropylcarbamate (2.5g,13.2mmol) in toluene (25mL) was added PPh3(4.15g,15.8mmol) and isoindoline-1, 3-dione (2.72g,18.5 mmol). The mixture was cooled to 0-5 ℃ and DIAD (3.2g,15.8mmol) was added dropwise. The reaction mixture was stirred at ambient temperatureStirring for 3 hours. The precipitated solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:9 to 1:1) to give (R) -3- (1, 3-bisoxoisoindolin-2-yl) -2-methylpropylcarbamic acid tert-butyl ester.1H NMR(400MHz,CDCl3):δ7.85(m,2H),7.47(m,2H),5.23(br s,1H),3.64(m,2H),3.03(br s,2H),2.13(m,1H),1.43(s,9H),0.96(d,J=6.4Hz,3H)。
To a solution of (R) -3- (1, 3-bis-oxoisoindolin-2-yl) -2-methylpropylcarbamic acid tert-butyl ester (40g,8.83mmol) in MeOH (200mL) was added methylamine solution (7.8g, 30% MeOH solution). The reaction mixture was heated at 60 ℃ for 6 hours. The solvent was removed under reduced pressure. The residue was suspended in diethyl ether (300mL) and then stirred for 0.5 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to give (S) -3-amino-2-methylpropylcarbamic acid tert-butyl ester.
To a solution of tert-butyl (S) -3-amino-2-methylpropylcarbamate (12.5g,66.5mmol) in DCM (250mL) was added TEA (10.3g,101.7 mmol). The mixture was cooled to 0-5 ℃ and 4- (dimethylamino) benzene-1-sulfonyl chloride (16g,72mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was washed with water and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1:9 to 3:7) to give (R) -3- (4- (dimethylamino) phenylsulfonylamino) -2-methylpropylcarbamic acid tert-butyl ester.1H NMR(400MHz,CDCl3):δ7.70(d,J=8.8Hz,2H),6.71(d,J=8.8Hz,2H),5.45(m,1H),4.72(m,1H),3.18(m,1H),3.04(s,6H),2.98(m,2H),2.75(m,1H),1.78(m,1H),1.41(s,9H),0.87(m,J=6.8Hz,3H)。
To a solution of (R) -3- (4- (dimethylamino) phenylsulfonylamino) -2-methylpropylcarbamic acid tert-butyl ester (21g,59.3mmol) in MeOH (150mL) was added 4N Cl/MeOH (150 mL). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure. The resulting solid was suspended in DCM (200mL) and saturated K was added2CO3Aqueous solution (150 mL). The mixture was stirred for 5 minutes and the organic layer was separated over anhydrous Na2SO4Drying and concentrating to obtain the compound (R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide.1H NMR(400MHz,CDCl3):δ7.70(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H),3.04(s,6H),2.98(m,1H),2.75(m,2H),2.58(m,1H),1.78(m,2H),0.87(m,J=7.2Hz,3H)。
A similar procedure was used to synthesize (S) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (an intermediate of compound a 76).
Pathway 34
To a solution of 6-chloro-N- ((R) -3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -1,2,3, 4-tetrahydronaphthalene-2-sulfonamide (100mg,200 μ M) in anhydrous NMP (4mL) at 0 ℃ NaH (24mg,600 μmol) was added, the mixture was stirred at ambient temperature for 20 minutes and it turned from a cloudy mixture to almost transparent during this time. Dichloride (21.3 μ L,200 μmol) was added and the mixture was heated to 80 ℃. After 40 minutes the reaction was quenched with brine and the aqueous layer was extracted with ethyl acetate (2 ×), the combined organics were washed with brine (3 ×), dried over sodium sulfate, filtered, and concentrated. Column chromatography (0-50% hexane + 1% diethylamine)/ethyl acetate) afforded the product (compound B21). C of MS (EI)25H35ClN4O4S2Found 555[ M + H]+。
Pathway 35
To the CH of trifluoromethanesulfonic acid 1- (4-fluoro-2-methoxyphenyl) piperazine (1.4g,6.8mmol)3To CN (15mL) solution was added 1- (1H-imidazol-1-ylsulfonyl) -3-methyl-1H-imidazol-3-ium ester (2.7g,6.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was then concentrated and the residue was purified by column chromatography to give 1- ((1H-imidazol-1-yl) sulfonyl) -4- (4-fluoro-2-methoxyphenyl) piperazine.
1- ((1H) at 0 ℃(ii) -Imidazol-1-yl) sulfonyl) -4- (4-fluoro-2-methoxyphenyl) piperazine (0.92g,2.7mmol) in DCM (10mL) was added CF3SO3Me (0.45g,2.7 mmol). The reaction mixture was stirred at ambient temperature for 5 hours and then concentrated, and the resulting product was washed with diethyl ether to give 1- ((4- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate.
To a solution of (R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (0.6g,2.2mmol) in CH3To a solution of CN (6mL) was added trifluoromethanesulfonic acid 1- ((4- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium ester (1.1g,2.2 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give (S) -N- (3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide.
To a solution of (S) -N- (3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide (771mg,1.42mmol) in NMP (7mL) was added NaH (140mg,3.48mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and dimethyl sulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (propane-3, 1-diyl) ester (820mg,2.1mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours, then cooled and poured into water. The resulting mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc 10:1) to give compound a 137. C of MS (EI)36H57FN6O5S2Found 737[ M + H [)]+。1H NMR(400MHz,CDCl3):δ7.62(d,J=8.8Hz,2H),7.16(m,2H),7.05(m,1H),6.86(d,J=8.8Hz,2H),4.35(m,2H),3.62(m,4H),3.19(m,2H),3.04(s,6H),2.87(m4H),2.46(m,5H),1.92(m,1H),1.79(m,2H),1.66(m,4H)。
The following compounds were synthesized in a similar manner:
pathway 36
To a solution of methyl (R) -2- ((tert-butoxycarbonyl) methyl) butyrate (4.8g,20.8mmol) in THF (50mL) was added LiBH4(0.7g,33 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was quenched with water (30mL), followed by dropwise addition of 1n hcl aqueous solution to adjust the pH to 2-3. The resulting mixture was extracted with ethyl acetate, and the extract was extracted with saturated NaHCO3The aqueous solution was washed, dried over anhydrous sodium sulfate and concentrated to give tert-butyl (R) -2- (hydroxymethyl) butylcarbamate.
To a solution of tert-butyl (R) -2- (hydroxymethyl) butylcarbamate (3.4g,16.7mmol) in toluene (40mL) was added PPh3(6.2g,17.4mmol) and isoindoline-1, 3-dione (3.7g,25 mmol). The mixture was cooled to 0-5 ℃ and DIAD (4.3g,22mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hours. The resulting precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 9:1 to 1:1) to give 1- (4-fluoro-2-methoxyphenyl) -4- (2-methyl-1H-imidazol-1-ylsulfonyl) piperazine.
To a solution of 1- (4-fluoro-2-methoxyphenyl) -4- (2-methyl-1H-imidazol-1-ylsulfonyl) piperazine (3.8g,11.4mmol) in EtOH (70mL) was added hydrazine hydrate (1.1g, 80%). The reaction mixture was refluxed for 6 hours. The resulting product was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1N aqueous NaOH (20mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give tert-butyl (S) -2- (aminomethyl) butylcarbamate.
To a solution of tert-butyl (S) -2- (aminomethyl) butylcarbamate (1.87g,9.2mmol) in DCM (20mL) was added TEA (1.01g,10.1 mol). The mixture was cooled to 0-5 ℃ and 4- (dimethylamino) benzene-1-sulfonyl chloride (2.0g,9.2mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was washed with water and then concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 9:1 to 7:3) to give tert-butyl (R) -2- ((4- (dimethylamino) phenylsulfonylamino) methyl) butylcarbamate.
To a solution of (R) -tert-butyl 2- ((4- (dimethylamino) phenylsulfonylamino) methyl) butylcarbamate (2.9g,7.5mmol) in MeOH (10mL) was added 4N Cl/MeOH (15 mL). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure. The resulting product was suspended in DCM (100mL) and saturated K was added2CO3Aqueous solution (450 mL). The mixture was stirred for 5 minutes. The DCM layer was separated, dried over anhydrous sodium sulfate, and concentrated to give (R) -N- (2- (aminomethyl) butyl) -4- (dimethylamino) benzenesulfonamide.
To a solution of (R) -N- (2- (aminomethyl) butyl) -4- (dimethylamino) benzenesulfonamide (0.9g,3.2mmol) in CH3CN (9mL) solution was added with 1- ((6-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium trifluoromethane sulfonate (0.59g,3.2 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 8:1 to 2:1) to give (S) -6-chloro-N- (2- ((4- (dimethylamino) phenylsulfonylamino) methyl) butyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide.
To a solution of (S) -6-chloro-N- (2- ((4- (dimethylamino) phenylsulfonylamino) methyl) butyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (0.8g,1.5mmol) in NMP (3mL) was added NaH (159mg,3.9mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and cyclopropane dimesylate was added1, 1-Azoalkylbis (methylene) ester (510mg,2.0 mmol). The reaction mixture was stirred at 70 ℃ for 2 hours. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc 15:1) to give compound a 182. LC-MS M/z 708.2[ M + H ]]+.1H NMR(400MHz,CDCl3):δ7.59(m,2H),7.15(m,2H),7.05(m,1H),6.68(m,2H),4.34(m,2H),3.55(m,4H),3.19(m,6H),3.04(s,6H),2.87(m,4H),2.15(m,4H),1.89(m,10H),1.32(m,8H),0.88(m,3H)。
Pathway 37
To (S) -5- ((6-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -9- ((4- (dimethylamino) phenyl) sulfonyl) -7-methyl-1, 5, 9-triazacyclododecane-1-carboxylic acid benzyl ester (25mg) was added HBr (33% in acetic acid, 0.5 mL). After 30 minutes at ambient temperature the mixture was diluted with diethyl ether and water (1:1 mix, 10mL) and the organic layer was removed. The aqueous layer was washed with diethyl ether (1 × 5mL), basified to pH-12 with NaOH (4N), followed by extraction with DCM (3 × 2 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Hexane (2mL) was added and then concentrated to precipitate the product. Drying under vacuum to give compound a 183. C of MS (EI)27H40ClN5O4S2Found value of 598[ M + H]+。
Pathway 38
To a solution of 3,3' -azaalkanediylpropropan-1-ol (1.0g,7.5mmol) in DCM (20mL) was added isobutyraldehyde (1.22g,11.3 mmol). The mixture was stirred at ambient temperature for 30 minutes. Acetic acid (1.8g,30.1mmol) was added and the mixture stirred for another 30 minutes. Sodium triacetoxyborohydride (6.40g,30.1mmol) was then added and the reaction mixture was stirred at ambient temperature overnight. The mixture was adjusted to pH 1-2 with 3n hcl aqueous solution and then stirred for 1 hour. To the mixture was added 20% aqueous NaOH (to adjust the pH to 10-11) and then it was extracted with DCM (50 mL). The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 3,3' - (isobutylazelidinyl) bis (propan-1-ol).
To a solution of 3,3' - (isobutylazalidinyl) bis (propan-1-ol) (780mg,4.1mmol) in DCM (10mL) was added NEt3(820mg,8.2 mmol). Then MsCl (935mg,8.2mmol) was added slowly at 0 ℃. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with DCM (20mL) and then washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give 3,3' - (isobutylazelidinyl) bis (propane-3, 1-diyl) dimesylate.
To a solution of (S) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonylamino) -2-methylpropyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (0.515g,1.03mmol) in anhydrous N-methylpyrrolidone was added NaH (0.25g,2.26mmol) at ambient temperature. The mixture was heated with stirring at 80 ℃ for 30 minutes and then cooled to ambient temperature. 3,3' - (isobutylazanediyl) bis (propane-3, 1-diyl) dimesylate (0.5g,1.5mmol) was added and the reaction mixture was stirred at 80 ℃ for 2 hours. The reaction was quenched with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give compound a 152. C of MS (EI)31H48ClN5O4S2Found 654.4[ M + H ]]+。1HNMR(400MHz,CDCl3):δ7.59(d,2H),7.16(m,2H),7.04(m,1H),6.69(d,2H),4.32(m,2H),3.60(m,4H),3.31(m,3H),3.04(s,6H),2.90(m,4H),2.27(m,4H),1.93(m,2H),1.79(m,1H),0.87(m,9H)。
The following compounds were synthesized in a similar manner:
pathway 39
To 4-fluoro-2-methoxyaniline (25.0g,177mmol), K in i-PrOH (250mL)2CO3(36.7g,266mmol) and NaI (10.6g,0.07mmol) was added bis (2-chloroethyl) amine hydrochloride (47g,177 mmol). The reaction mixture was refluxed overnight. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 10:1) to give 1- (4-fluoro-2-methoxyphenyl) piperazine. MS M/z 212.36[ M + H ]]+。
To a solution of 1- (4-fluoro-2-methoxyphenyl) piperazine (4.0g,19mmol) in MeCN (40mL) was added 2, 3-dimethyl-1- (2-methyl-1H-imidazol-1-ylsulfonyl) -1H-imidazol-3-ium (7.5g,19 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 20:1) to give 1- (4-fluoro-2-methoxyphenyl) -4- (2-methyl-1H-imidazol-1-ylsulfonyl) piperazine. MS M/z 355.36[ M + H ]]+。
To a solution of 1- (4-fluoro-2-methoxyphenyl) -4- (2-methyl-1H-imidazol-1-ylsulfonyl) piperazine (6.0g,17mmol) in DCM (60mL) was added CF3SO3Me (2.78g,17 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was washed with diethyl ether to give 1- (4- (4-fluoro-2-methoxyphenyl) piperazin-1-ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate.
To trifluoromethanesulfonic acid 1- (4- (4-fluoro-2-methoxyphenyl) piperazin-1-ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester (740mg,2.3mmol) in CH3To CN (8mL) solution was added tert-butyl 3- ((3-aminopropyl) (cyclohexylmethyl) amino) propylcarbamate (1.17g,2.3 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 8:1 to 2:1) to giveTert-butyl 3- ((cyclohexylmethyl) (3- (4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonylamino) propyl) amino) propylcarbamate.
To a solution of tert-butyl 3- ((cyclohexylmethyl) (3- (4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonylamino) propyl) amino) propylcarbamate (600mg,1mmol) in DCM (30mL) was added TFA (30 mL). The mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was dissolved in ethyl acetate and then saturated NaHCO3And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide.
To a solution of N- (3- ((3-aminopropyl) (cyclohexylmethyl) amino) propyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide (416mg,0.83mmol) in DCM (5mL) was added Et3N (170mg,1.66mmol) and 4- (dimethylamino) benzenesulfonyl chloride (365mg,1.66 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and purified by column chromatography (petroleum ether/EtOAc ═ 8:1 to 2:1) to give N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) phenylsulfonylamino) propyl) amino) propyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide.
To a solution of N- (3- ((cyclohexylmethyl) (3- (4- (dimethylamino) phenylsulfonylamino) propyl) amino) propyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide (320mg,0.45mmol) in NMP (3mL) was added NaH (53mg,1.32mmol, 60% dispersion). The mixture was stirred at 80 ℃ for 0.5 h, then cooled to 70 ℃ and cyclopropane-1, 1-diylbis (methylene) dimesylate (170mg,0.66mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc 15:1) to give compound a 193. C of MS (EI)37H57FN6O5S2Found 745.0[ M + H]+。1H NMR(400MHz,CDCl3):d 7.57(t,2H),6.64(t,1H),6.63(br s,4H),3.86(s,3H),3.19(m,4H),3.04(m,8H),2.87(m,12H),2.36(m,2H),1.56(m,15H),0.43(m,4H)。
Pathway 40
To a solution of tert-butyl (S) -3-amino-2-methylpropylcarbamate (4.0g,21.3mmol) in THF (20mL) and water (20mL) was added CbzOSu (5.83g,23.5 mmol). Aqueous NaOH (4N) was added to adjust the pH to 11. The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with water (15mL) and then extracted with ethyl acetate (50 mL). The organic layer was washed with 1N aqueous HCl, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give (2-methylpropane-1, 3-diyl) (S) -dicarbamic acid benzyl tert-butyl ester.
To a solution of (2-methylpropan-1, 3-diyl) (S) -dicarbamic acid benzyl tert-butyl ester (4.5g,14.0mmol) in DCM (25mL) was added TFA (20 mL). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated and the residue was dissolved in DCM (50 mL). The resulting solution was saturated with K2CO3The aqueous solution was washed, and the DCM layer was dried over anhydrous sodium sulfate and concentrated to give (R) -3-amino-2-methylpropylcarbamic acid benzyl ester.
To the solution of (R) -benzyl 3-amino-2-methylpropylcarbamate (2.7g,12.2mmol) in CH3CN (25mL) solution was added 1- (6-chloro-3, 4-dihydroisoquinolin-2 (1H) -ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium (5.7g,12.2 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give benzyl (S) -3- (6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) -2-methylpropylcarbamate.
(S) -3- (6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) -2-methylpropylcarbamic acid benzyl ester (2.7g,6.0mmol) was dissolved in HBr (48%)/HOAc (20 mL). The mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with water (100mL) and then extracted with ether (50 mL). The aqueous layer was basified to pH 10 with NaOH. The resulting mixture was extracted with DCM (100 mL). The DCM layer was dried over anhydrous sodium sulfate and concentrated to give (S) -N- (3-amino-2-methylpropyl) -6-chloro-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide.
To a solution of (S) -N- (3-amino-2-methylpropyl) -6-chloro-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (0.6g,1.9mmol) and TEA (270mg,2.7mmol) in DCM (6mL) at 0 deg.C was added benzo [ d ] isoxazole-5-sulfonyl chloride (420mg,1.9 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was washed with water and then concentrated. The residue was purified by column chromatography to give (S) -N- (3- (6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) -2-methylpropyl) benzo [ d ] isoxazole-5-sulfonamide.
To (S) -N- (3- (6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) -2-methylpropyl) benzo [ d]To a solution of isoxazole-5-sulfonamide (0.61g,1.22mmol) in NMP (6mL) was added NaH (122mg,3.05mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and 3,3' - (cyclohexylmethylazanediyl) bis (propane-3, 1-diyl) dimesylate (0.74g,1.83mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours. The mixture was cooled and poured into water. The resulting mixture was extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 12:1) to afford compound a 180. LC-MS (ESI) M/z 692.2[ M + H [ ]]+.1HNMR(400MHz,CDCl3):δ7.84(S,1H),7.61(m,1H),7.13(m,3H),6.69(m,2H),4.32(m,2H),3.66(m,5H),3.21(m,5H),2.91(m,4H),2.77(m,4H),1.91(m,4H),1.57(m,6H),1.13(m,6H),0.89(m,3H)。
The following compounds were synthesized in a similar manner:
pathway 41
To a suspension of Mg (4.4g,181mmol) in THF (200mL) was added 1-bromo-2-methoxybenzene (40g,214 mmol). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 0 ℃ and a solution of tert-butyl 3-oxopiperidine-1-carboxylate (35.5g,181mmol) in THF was added. The reaction mixture was stirred at ambient temperature for 2 hours. The residue was purified by column chromatography to give tert-butyl 3-hydroxy-3- (2-methoxyphenyl) piperidine-1-carboxylate.1H NMR(400MHz,CDCl3):δ7.48(m,1H),7.32(m,1H),6.98(m,2H),4.08(m,1H),3.96(s,3H),3.82(m,1H),3.31(s,1H),2.98(m,1H),2.25(m,1H),1.99(m,2H),1.62(m,2H),1.63(m,9H)。
A solution of tert-butyl 3-hydroxy-3- (2-methoxyphenyl) piperidine-1-carboxylate (23.0g,75mmol) and triethylsilane (44mL) in DCM (230mL) was cooled to-30 ℃ and TFA (27mL) was added. The reaction mixture was stirred at-30 ℃ for 2.5 hours, and then allowed to warm to ambient temperature and stirred for an additional 3.5 hours. The mixture was poured into ice water, and the solution was adjusted to pH 9 with saturated aqueous sodium hydroxide solution. The resulting mixture was extracted 3 times with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give 3- (2-methoxyphenyl) piperidine.
A solution of 3- (2-methoxyphenyl) piperidine (6.5g,34mmol) and D-tartaric acid (5.1g,34mmol) in MeOH (25mL) was refluxed for 2 hours. The mixture was cooled to ambient temperature and filtered to give the tartrate salt. The tartrate salt was recrystallized twice in MeOH and then treated with aqueous NaOH. The resulting mixture was extracted with DCM. The DCM layer was dried over anhydrous sodium sulfate and concentrated to give (S) -3- (2-methoxyphenyl) piperidine.
(S) -3- (2-methoxyphenyl) piperidine (500mg,2.6mmol) was stirred at ambient temperature overnight with a solution of trifluoromethanesulfonic acid 2, 3-dimethyl-1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) -1H-imidazol-3-ium ester (1.1g,2.7mmol) in MeCN (15 mL). The solvent is removed. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 20:1) to give (S) -3- (2-methoxyphenyl) -1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) piperidine. LC-MS (ESI) M/z 336.06[ M + H [ ]]+。
To a solution of (S) -3- (2-methoxyphenyl) -1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) piperidine (800g,2.4mmol) in DCM (10mL) was added CF3SO3Me (398mg,2.4 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was washed with diethyl ether to give trifluoromethylAlkanesulfonic acid (S) -1- (3- (2-methoxyphenyl) piperidin-1-yl) -2, 3-dimethyl-1H-imidazol-3-ium ester.
To trifluoromethanesulfonic acid (S) -1- (3- (2-methoxyphenyl) piperidin-1-yl) -2, 3-dimethyl-1H-imidazol-3-ium ester (1g,2mmol) in CH3CN (24mL) solution was added (R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (0.55g,2 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 8:1 to 2:1) to give (S) -N- ((S) -3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -3- (2-methoxyphenyl) piperidine-1-sulfonamide.
To a solution of (S) -N- ((S) -3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -3- (2-methoxyphenyl) piperidine-1-sulfonamide (454mg,0.86mmol) in NMP (14mL) was added NaH (104mg,2.6mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and dimethyl sulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (propane-3, 1-diyl) ester (500mg,1.3mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours. The mixture was cooled to 0-5 ℃ and poured into water. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC to give compound a 210. LC-MS (ESI) M/z 718.17[ M + H [ ]]+。1HNMR(400MHz,CDCl3):δ7.60(m,2H),7.23(m,2H),6.95(m,2H),6.68(m,2H),3.82(s,3H),3.73(m,5H),3.26(m,4H),3.12(s,6H),2.76(m,5H),2.36(m,4H),1.76(m,9H),1.33(m,10H),0.86(m,6H)。
The following compounds were synthesized in a similar manner:
pathway 42
In 1, 4-dioxane (50mL) and H23- (4, 4) in O (10mL)5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (10.92g,35mmol), 1-bromo-3-methoxybenzene (6.6g,35mmol) and Cs2CO3(3.44g,106mmol) Pd (dppf) Cl was added to the solution2(1.32g,1.75 mmol). The reaction mixture was stirred at 80 ℃ overnight. The solvent is removed. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 10:1) to give 3- (3-methoxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester. LC-MS (ESI) M/z290.12[ M + H [ ]]+。1HNMR(400MHz,CDCl3):δ7.26(m,1H),6.96(m,1H),6.89(s,1H),6.81(m,1H),6.19(s,1H),4.25(s,2H),3.81(s,3H),3.54(m,2H),2.30(s,2H),1.49(s,9H)。
The mixture is brought to ambient temperature under H2Stir for 4 hours at ambient. The mixture was filtered and the filtrate was concentrated to give tert-butyl 3- (3-methoxyphenyl) piperidine-1-carboxylate.1HNMR(400MHz,CDCl3):δ7.25(m,1H),6.81(m,3H),3.99(m,2H),3.73(s,3H),2.65(m,1H),2.55(m,1H),2.50(m,2H),1.98(m,1H),1.65(m,2H),1.44(s,9H)。
A solution of tert-butyl 3- (3-methoxyphenyl) piperidine-1-carboxylate (7.85g,27mmol) in HCl/MeOH (80mL) was stirred at ambient temperature for 4 hours. The mixture was treated with water and then adjusted to pH 12 with 3n naoh aqueous solution. The resulting mixture was extracted with EtOAc (100 mL. times.2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 3- (3-methoxyphenyl). LC-MS (ESI) M/z 192.09[ M + H [ ]]+。
To a solution of D- (-) -tartaric acid (2.5g,16.7mmol) in MeOH (12.5mL) was added 3- (3-methoxyphenyl) piperidine (3.2g,16.7 mmol). The mixture was stirred at 80 ℃ for 24 hours and then cooled to ambient temperature. The resulting precipitate was collected by filtration, then recrystallized three times in MeOH to give (S) -3- (3-methoxyphenyl) piperidine.
To a solution of (S) -3- (3-methoxyphenyl) piperidine (1.28g,6.7mmol) in CH3CN (10mL) solution was added trifluoromethanesulfonic acid 1- (1H-imidazol-1-ylsulfonyl) -3-methyl-1H-imidazol-3-ium ester (2.87g,7.3 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent is removed. The residue was purified by column chromatography (petroleum ether/EtOAc ═9:1 to 8:2) to obtain (S) -3- (3-methoxyphenyl) -1- (2-methyl-1H-imidazol-1-ylsulfonyl) piperidine.1H NMR(400MHz,CDCl3):δ7.27(m,1H),7.21(s,1H),6.93(s,1H),6.79(m,2H),6.72(s,1H),3.93(m,2H),3.82(s,3H),2.68(m,1H),2.65(m,2H),2.62(s,3H),2.06(m,1H),1.95(m,1H),1.82(m,1H),1.62(m,1H)。
To a solution of (S) -3- (3-methoxyphenyl) -1- (2-methyl-1H-imidazol-1-ylsulfonyl) piperidine (1.6mg,4.7mmol) in DCM (20mL) was added CF3CO2Me (782mg,4.7 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent is removed. The resulting product was washed with diethyl ether to give (S) -1- (3- (3-methoxyphenyl) piperidin-1-ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate.
To trifluoromethanesulfonic acid (S) -1- (3- (3-methoxyphenyl) piperidin-1-ylsulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester (1.1g,2.2mmol) in CH3CN (11mL) solution was added (R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (896mg,33 mmol). The mixture was stirred at ambient temperature overnight. The solvent is removed. The residue was purified by column chromatography to give (S) -N- ((S) -3- (4- (dimethylamino) phenylsulfonylamino) -2-methylpropyl) -3- (3-methoxyphenyl) piperidine-1-sulfonamide.1H NMR(400MHz,CDCl3):δ7.68(m,2H),7.28(m,1H),6.85(m,1H),6.80(m,2H),6.68(m,2H),4.81(m,2H),3.82(s,3H),3.76(m,2H),3.12(m,1H),3.07(s,6H),2.82(m,4H),2.11(m,1H),1.93(m,2H),1.77(m,1H),1.29(m,3H),0.91(m,3H)。
To a solution of (S) -N- ((S) -3- (4- (dimethylamino) phenylsulfonylamino) -2-methylpropyl) -3- (3-methoxyphenyl) piperidine-1-sulfonamide (550mg,1.05mmol) in NMP (6mL) was added sodium hydride (75.6mg,3.15 mmol). The mixture was stirred at 80 ℃ for 30 minutes. The mixture was cooled to 70 ℃ and a solution of dimethyl sulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (propane-3, 1-diyl) ester (606mg,1.57mmol) in NMP (3mL) was added. The reaction mixture was stirred at 70 ℃ for 1 hour. The mixture was cooled and poured into water. The mixture was cooled to ambient temperature and poured into water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with water (15 mL. times.2),dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EtOAc/petroleum ether ═ 1:15 to 1:5) to give compound a 209. LC-MS (ESI) M/z 719.2[ M + H [ ]]+。1H NMR(400MHz,CDCl3):δ7.61(m,2H),7.28(m,2H),6.84(m,3H),6.70(m,2H),3.83(s,3H),3.70(m,2H),3.55(m,2H),3.30(m,1H),3.11(s,9H),2.79(m,5H),2.41(m,1H),2.33(m,3H),2.05(m,8H),1.67(m,4H),1.27(m,7H),0.94(m,3H),0.85(m,2H)。
Pathway 43
To a solution of (S) -N- (3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -4- (4-fluoro-2-methoxyphenyl) piperazine-1-sulfonamide (900mg,1.65mmol) in NMP (5mL) was added NaH (198mg,4.92mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and (S) -dimethylsulfonic acid 3,3' - (1-cyclohexylethylaminodiyl) bis (propane-3, 1-diyl) ester (844mg,2.49mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours, then cooled to 0-5 ℃ and poured into water. The resulting mixture was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 15:1) to give compound a 203. LC-MS (ESI) M/z 751.33[ M + H [ ]]+。1H NMR(400MHz,CDCl3):δ7.68(m,2H),6.92(m,1H),6.78(m,4H),3.92(s,4H),3.86(m,1H),3.62(m,1H),3.40(m,2H),3.19(m,3H),3.04(s,9H),2.87(m2H),2.26(m,3H),1.92(m,3H),1.79(m,4H),1.66(m,2H),1.54(m,2H),1.38(m,4H),1.26(m,5H),0.98(m,3H),0.83(m,4H)。
The following compounds were synthesized in a similar manner:
pathway 44
To a solution of 1-bromo-4-fluoro-2-methoxybenzene (910mg,4.4mmol) and 1M KHMDS (18mL,18mmol) in 1, 4-dioxane (9mL) was added tert-butyl (3R,5R) -3, 5-dimethylpiperazine-1-carboxylate (950mg,4.4 mmol). The reaction mixture was stirred at 100 ℃ for 3 hours. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 20:1) to give (3R,5R) -4- (3-fluoro-5-methoxyphenyl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (ESI) M/z 339.0[ M + H ]]+。
To a solution of (3R,5R) -4- (3-fluoro-5-methoxyphenyl) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (800mg,2.4mmol) in DCM (4mL) was added TFA (4 mL). The mixture was stirred at ambient temperature for 1 hour. The solvent is removed. The residue was dissolved in DCM (50mL) and then saturated with K2CO3And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give (2R,6R) -1- (3-methoxy-5-methylphenyl) -2, 6-dimethylpiperazine.
To a solution of (2R,6R) -1- (3-methoxy-5-methylphenyl) -2, 6-dimethylpiperazine (500mg,2.1mmol) in MeCN (5mL) was added trifluoromethanesulfonic acid 2, 3-dimethyl-1- ((2-methyl-1H-imidazol-1-yl) sulfonyl) -1H-imidazol-3-ium ester (825mg,2.1 mmol). The reaction mixture was stirred at ambient temperature overnight. The solvent is removed. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 20:1) to give (2R,6R) -1- (3-fluoro-5-methoxyphenyl) -2, 6-dimethyl-4- ((2-methyl-1H-imidazol-1-yl) sulfonyl) piperazine. LC-MS (ESI) M/z 383.53[ M + H [ ]]+。
To a solution of (2R,6R) -1- (3-methoxy-5-methylphenyl) -2, 6-dimethylpiperazine (450mg,1.2mmol) in DCM (5mL) was added CF3SO3Me (193mg,1.2 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was washed with diethyl ether to give trifluoromethanesulfonic acid 1- (((3R,5R) -4- (3-fluoro-5-methoxyphenyl) -3, 5-dimethylpiperazin-1-yl) sulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester.
To trifluoromethanesulfonic acid 1- (((3R,5R) -4- (3-fluoro-5-methoxyphenyl) -3, 5-dimethylpiperazin-1-yl) sulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium ester (500mg,0.91mmol) in CH3CN (5mL) solution was added(R) -N- (3-amino-2-methylpropyl) -4- (dimethylamino) benzenesulfonamide (248mg,0.91 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 8:1 to 2:1) to give (2S,6S) -N- ((S) -3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -4- (3-fluoro-5-methoxyphenyl) -2, 6-dimethylpiperazine-1-sulfonamide. LC-MS (ESI) M/z 572.4[ M + H [ ]]+。
To a solution of (2S,6S) -N- ((S) -3- ((4- (dimethylamino) phenyl) sulfonamido) -2-methylpropyl) -4- (3-fluoro-5-methoxyphenyl) -2, 6-dimethylpiperazine-1-sulfonamide (430mg,0.75mmol) in NMP (4mL) was added NaH (91mg,2.3mmol, 60%). The mixture was stirred at 80 ℃ for 0.5 h. The mixture was cooled to 70 ℃ and dimethyl sulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (propane-3, 1-diyl) ester (435mg,1.1mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hours. The mixture was cooled and poured into water. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc 15:1) to give compound a 200. LC-MS (ESI) M/z 764.3[ M + H [ ]]+。1HNMR(400MHz,CDCl3):δ7.60(d,2H),6.69(d,2H),6.32(d,3H),3.78(s,3H),3.06(q,2H),3.04(s,8H),3.00(s,2H),2.87(d,2H),2.76(s,2H),2.34(br s,4H),2.09(br s,2H),1.33(s,17H),1.04(d,7H),0.93(d,3H)。
(S) -3,3' - (1-Cyclohexylethylazelidinyl) diprop-1-ol (intermediate of Compounds A203, A190, A207)
To a solution of (S) -1-cyclohexylethylamine (4.0g,31.46mmol) in methanol (50mL) was added methyl acrylate (8.1g,94.38 mmol). The reaction mixture was stirred at 45 ℃ for 72 hours. The mixture was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc ═ 30:1) to give dimethyl (S) -3,3' - (1-cyclohexylethylazelidinyl) dipropionate.
To a solution of dimethyl (S) -3,3' - (1-cyclohexylethylazelidinyl) dipropionate (4.0g,13.37mmol) in THF (50mL) was added LiBH4(1.45g,66.84 mmol). The reaction mixture was stirred at 60 ℃ for 2 hours. The mixture was cooled to 0-5 ℃ and quenched with water (30 mL). The mixture was adjusted to pH 3 with 1N aqueous hydrochloric acid and stirred for 30 minutes. The resulting mixture was washed with dichloromethane. The aqueous layer was adjusted to pH 9-10 with saturated aqueous sodium carbonate and then extracted with DCM (3 ×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give (S) -3,3' - (1-cyclohexylethylazelidinyl) diprop-1-ol.1H NMR(400MHz,CDCl3):δ3.66(s,1H),2.82(m,2H),2.42(m,2H),2.21(m,1H),1.96(m,2H),1.67(m,4H),1.22(m,4H),0.91(m,3H),0.81(m,1H),0.72(m,1H)。
The following compounds were synthesized in a similar manner: (R) -3,3'- (1-cyclohexylethylazelidinyl) diprop-1-ol (intermediate of Compound A191) and (S) -3,3' - ((1-phenylethyl) azelidinyl) bis (propan-1-ol) (intermediate of Compound A205).
6-chloro-N- (((1R,2S) -2- (4- (dimethylamino) phenylsulfonylamino) cyclobutyl) methyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfanilamide (intermediate of Compound B22)
To a suspension of cis-3-azabicyclo [3.2.0] heptane-2, 4-dione (32.8g,200mmol) and quinine (71.4g,220mmol) in toluene (1L) was added benzyl alcohol (64.9g,600mmol) dropwise over a period of 0.5 hours at-55 deg.C. The reaction mixture was stirred at-55 ℃ for 96 hours. The resulting clear solution was concentrated to dryness, and the residue was dissolved in diethyl ether (1.2L). The solution was washed with 2N aqueous HCl (1L), the organic layer was extracted with saturated sodium bicarbonate (500 x5mL), and the resulting combined aqueous phases were washed with diethyl ether (500mL) to remove traces of benzyl alcohol. The aqueous phase was acidified with 8N aqueous HCl and extracted with DCM (1.0 L.times.2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give (1S,2R) -2 (benzyloxycarbonyl) cyclobutanecarboxylic acid.
To (1S,2R) -2- (benzyloxycarbonyl) cyclobutanecarboxylic acid (40.1g,171.4mmol) and triethylamine (26.0g,257mmol) in dichloroethane at 0 deg.C(400mL) solution DPPA (51.8g,188.5mmol) was added dropwise. The mixture was stirred at ambient temperature for 2 hours, then washed with water and passed over anhydrous NaSO4And (5) drying. To the organic solution was added BnOH (18.5g,171mmol) and triethylamine (34.6g,342 mmol). The reaction mixture was refluxed overnight and then diluted with DCM (500 mL). With 1N aqueous HCl (1L) and saturated NaHCO3The mixture is washed with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give benzyl (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate.
To a solution of benzyl (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate (20g,59mmol) in THF (100mL) at 0 deg.C was added an aqueous solution of 4N NaOH (50 mL). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with water (30mL) and then extracted with diethyl ether (50mLx 2). The aqueous layer was acidified with 3n hcl aqueous solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated to give (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylic acid.1HNMR(400MHz,CDCl3):δ7.34(m,5H),5.12(m,2H),4.62(m,1H),3.58(m,1H),2.28(m,2H),1.89(m,2H)。
To (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylic acid (4.0g,16.1mmol) and K2CO3To a solution of (4.4g,32mmol) in DMF (40mL) was added MeI (2.96g,20.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was poured into water (150mL) and extracted with ether (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate.1H NMR(400MHz,CDCl3):δ7.34(m,5H),5.69(m,1H),5.08(s,2H),4.62(m,1H),3.66(s,3H),3.38(m,1H),2.32(m,2H),1.99(m,2H)。
To a solution of methyl (1R,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate (8.9g,33.8mmol) in MeOH (250mL) was added NaOMe (9.1g,169 mmol). The mixture was heated at 45 ℃ for 4 hours, then cooled to 0 ℃ and HOAc (10.2g,169mmol) was added dropwise. The mixture was then poured into water (500mL) and extracted with ethyl acetate (300 mL). The extract is extracted with saturated NaHCO3The aqueous solution was washed and dried over anhydrous sodium sulfate. The organic solution was concentrated and the residue was purified by column chromatography to give methyl (1S,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate.1HNMR(400MHz,CDCl3):δ7.34(m,5H),5.08(m,3H),4.38(m,1H),3.72(s,3H),3.38(m,1H),2.32(m,2H),1.89(m,2H)。
To a solution of methyl (1S,2S) -2- (benzyloxycarbonylamino) cyclobutanecarboxylate (1.3g,4.9mmol) in THF (10mL) was added LiBH4(0.38g,9.8 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, then poured into water (15mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give benzyl (1S,2S) -2- (hydroxymethyl) cyclobutylcarbamate.1H NMR(400MHz,CDCl3):δ7.34(m,5H),5.08(m,3H),3.72(m,1H),3.57(m,2H),2.32(m,2H),1.89(m,2H),1.45(m,1H)。
To (1S,2S) -2- (hydroxymethyl) cyclobutylcarbamic acid benzyl ester (1.1g,4.94mmol), PPh at 0 deg.C3To a solution of (1.5g,5.9mmol) and isoindoline-1, 3-dione (1.0g,6.9mmol) in toluene (10mL) was added DIAD (1.2g,5.9 mmol). The reaction mixture was stirred for 3 hours. The precipitate was filtered off and the filtrate was concentrated and purified by column chromatography to give benzyl (1S,2R) -2- ((1, 3-bisoxoisoindolin-2-yl) methyl) cyclobutylcarbamate.
To a solution of benzyl (1S,2R) -2- ((1, 3-bis-oxoisoindolin-2-yl) methyl) cyclobutylcarbamate (2.0g,5.5mmol) in EtOH (40mL) was added hydrazine hydrate (0.64 g). The reaction mixture was refluxed for 3 hours. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was dissolved in 1N aqueous HCl (30mL) and washed with diethyl ether (20 mL). The aqueous layer was adjusted to pH 10. The resulting mixture was extracted with DCM (50 mL. times.2). The combined organics were dried over anhydrous sodium sulfate and concentrated to give benzyl (1S,2R) -2- (aminomethyl) cyclobutylcarbamate.
To a solution of (1S,2R) -benzyl 2- (aminomethyl) cyclobutylcarbamate (0.8g,3.4mmol) in CH3CN (10mL) solution was added with 1- ((6-chloro-3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl) -2, 3-dimethyl-1H-imidazol-3-ium trifluoromethane sulfonate (2.4g,5.12 mmo)l). The reaction mixture was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by column chromatography to give benzyl (1S,2R) -2- ((6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) methyl) cyclobutylcarbamate.
To a 40% HBr solution in HOAc (10mL) was added benzyl (1S,2R) -2- ((6-chloro-1, 2,3, 4-tetrahydroisoquinoline-2-sulfonylamino) methyl) cyclobutylcarbamate (1.2g,2.6 mmol). The mixture was stirred for 3 hours, then poured into water (50mL) and washed with ether. The aqueous layer was adjusted to pH 10 with 8n naoh aqueous solution. The mixture was extracted with DCM (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give N- (((1R,2S) -2-aminocyclobutyl) methyl) -6-chloro-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide.
To N- (((1R,2S) -2-aminocyclobutyl) methyl) -6-chloro-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (0.66g,2.0mmol) and NEt at 0 deg.C3To a solution of (350mg,3.5mmol) in DCM (5mL) was added 4- (dimethylamino) benzenesulfonyl chloride (426mg,2.0 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated. The residue was dissolved in DCM and washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 6-chloro-N- (((1R,2S) -2- (4- (dimethylamino) phenylsulfonylamino) cyclobutyl) methyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide.1HNMR(400MHz,CDCl3):δ7.77(m,2H),7.18(m,2H),7.05(m,1H),6.75(m,2H),5.28(m,1H),5.05(m,1H),4.36(s,2H),3.50(m,2H),3.35(m,1H),3.15(m,1H),3.09(s,6H),2.92(m,3H),2.42(m,1H),2.03(m,1H),1.65(m,2H),1.25(m,1H)。
(S) -Methanesulfonic acid 3- ((cyclohexylmethyl) ((R) -2-methyl-3- (methylsulfonyloxy) propyl) amino) -2-methylpropyl ester (intermediate of Compound A178)
To a solution of methyl (S) -3-hydroxy-2-methylpropionate (4.0g,25.42mmol) and triethylamine (5.3g,50.84mmol) in DCM (60mL) at 0-5 deg.C was slowly added methanesulfonyl chloride (5.6g,10.20 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was then diluted with DCM (100mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give methyl (S) -2-methyl-3- (methylsulfonyloxy) propionate.
To a solution of (R) -methyl 2-aminopropionate hydrochloride (1.60g,10.20mmol) in acetonitrile (200mL) were added methyl (S) -2-methyl-3- (methylsulfonyloxy) propionate (4.2g,21.43mmol) and potassium carbonate (4.20g,30.60 mmol). The reaction mixture was refluxed for 16 hours and then filtered, and the filtrate was concentrated to give dimethyl (2R,2'S) -2,2' -azaalkanediyl-bis (methylene) dipropionate.
To a solution of (2R,2'S) -2,2' -azanediylbis (methylene) dipropionic acid dimethyl ester (650mg,3.0mmol) in DCM (10mL) was added cyclohexanecarboxaldehyde (336mg,3.0mmol) and sodium triacetoxyborohydride (954mg,4.50 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was quenched with water and adjusted to pH 10. The resulting mixture was extracted with DCM. The extract was concentrated and the residue was purified by column chromatography to give dimethyl (2R,2'S) -2,2' - (cyclohexylmethylazalidinyl) bis (methylene) dipropionate.
To a solution of (2R,2'S) -2,2' - (cyclohexylmethylazanediyl) bis (methylene) dipropionic acid dimethyl ester (350mg,1.28mmol) in THF (10mL) was added LiBH4(486mg,12.80 mmol). The reaction mixture was stirred at 80 ℃ overnight. The mixture was cooled and quenched with water. The resulting mixture was adjusted to pH 5 with 1N aqueous hydrochloric acid and stirred for 0.5 h, then adjusted to pH 10 and extracted three times with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated to give (2R,2'S) -2,2' - (cyclohexylmethylazanediyl) bis (methylene) diprop-1-ol.
To a solution of (2R,2'S) -2,2' - (cyclohexylmethylazaldi) bis (methylene) diprop-1-ol (153mg,0.59mmol) and triethylamine (0.12g,1.2mmol) in DCM (5mL) at 0 deg.C was added MsCl (135mg,1.18 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with DCM (15mL) and then washed with water (20mL × 2). The organics were dried over anhydrous sodium sulfate and concentrated to give (S) -methanesulfonic acid 3- ((cyclohexylmethyl) ((R) -2-methyl-3- (methylsulfonyloxy) propyl) amino)-2-methylpropyl ester. C of MS (EI)17H35NO6S2Found 414[ M + H]+。
The following compounds were synthesized in a similar manner: (2S,2' S) -Dimethanesulfonic acid ((cyclohexylmethyl) azaalkanediyl) bis (2-methylpropan-3, 1-diyl) ester (intermediate of Compound A160).
(R) -6-chloro-N- (4- (4- (dimethylamino) phenylsulfonylamino) butan-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (intermediate of Compound A148)
A solution of tert-butyl (R) -1-cyanoprop-2-ylcarbamate (13.0g,71mmol) saturated with anhydrous ammonia in ethanol (250mL) at 55psi H2Next, Raney-Ni (24g) was treated overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by column chromatography to give tert-butyl (R) -4-aminobut-2-ylcarbamate.
To a solution of tert-butyl (R) -4-aminobut-2-ylcarbamate (2.5g,13.3mmol) and triethylamine (1.33g,13.3mmol) in DCM (25mL) at 0-5 deg.C was slowly added a solution of 4- (dimethylamino) benzene-1-sulfonyl chloride (2.93g,13.3mmol) in DCM (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with DCM (50mL) and washed with water (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give tert-butyl (R) -4- (4- (dimethylamino) phenylsulfonylamino) but-2-ylcarbamate.
To a solution of tert-butyl (R) -4- (4- (dimethylamino) phenylsulfonylamino) butan-2-ylcarbamate (1.2g,3.2mmol) in DCM (15mL) was added TFA (7 mL). The mixture was stirred for 2 hours and the solvent was removed. The residue was dissolved in DCM (30mL) and then saturated NaHCO3And (4) washing with an aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to give (R) -N- (3-aminobutyl) -4- (dimethylamino) benzenesulfonamide (0.88g, quantitative).
To a solution of (R) -N- (3-aminobutyl) -4- (dimethylamino) benzenesulfonamide (0.88g,4.0 mm)ol) CH3CN (10mL) solution was added with 6-chloro-1, 2,3, 4-tetrahydroisoquinoline (1.98g,4.0 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture is concentrated and the residue is purified by column chromatography to give (R) -6-chloro-N- (4- (4- (dimethylamino) phenylsulfonylamino) butan-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide.
The following compounds were synthesized in a similar manner: (S) -6-chloro-N- (4- ((4- (dimethylamino) phenyl) sulfonamido) but-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (intermediate of compound a 147); (S) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonamido) butyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (intermediate of compound a 150); and (R) -6-chloro-N- (3- ((4- (dimethylamino) phenyl) sulfonamido) butyl) -3, 4-dihydroisoquinoline-2 (1H) -sulfonamide (intermediate of compound a 149).
(R) -1- (4-fluoro-2-methoxyphenyl) -2-methylpiperazine (intermediate for Compound A177)
To a solution of (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (5.37G,26.8mmol) and 1-bromo-4-fluoro-2-methoxybenzene (5.00G,24.4mmol) in toluene (50mL) was added sodium tert-butoxide (4.69G,48.8mmol) and subsequently BrettPhos cyclopalladated complex G3(66.4mg,0.0732 mmol). The mixture was sealed under nitrogen and stirred at 100 ℃, after 1 hour the mixture was cooled to ambient temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (0-40%, ethyl acetate/hexane) to give the product. C of MS (EI)17H25FN2O3Measured value 325[ M + H]+。
To (R) -4- (4-fluoro-2-methoxyphenyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.51g,1.6mmol) was added HCl (1.6mL,4N dioxane solution), and the mixture was allowed to stand at ambient temperature for 16 hours, followed by dilution with water (5mL) and ethyl acetate (5 mL). The organic layer was removed and washed with water (1 × 5 mL). The combined aqueous layers were washed with ethyl acetate (1 × 5mL) and NaOHBasified (5N to pH-12), extracted with DCM (3 × 5mL), dried over sodium sulfate, filtered, and concentrated to give (R) -1- (4-fluoro-2-methoxyphenyl) -2-methylpiperazine and used further without further purification. C of MS (EI)12H17FN2Measured value of O225 [ M + H]+。
The following compounds were synthesized in a similar manner:
1- (4-fluoro-2-methoxyphenyl) piperazine (intermediate of A137)
1- (2-methoxyphenyl) piperazine (intermediate of A154)
2- (piperazin-1-yl) benzonitrile (intermediate of A118)
1- (2, 6-dimethylphenyl) piperazine (intermediate of A119)
2- (4-fluoro-2-methyl) -2, 6-diazaspiro [3.3] heptane (intermediate of A161)
(S) -1- (4-fluoro-2-methylphenyl) -3-methylpiperazine (intermediate of A162)
(R) -1- (4-fluoro-2-methylphenyl) -3-methylpiperazine (intermediate of A163)
1- (2- (trifluoromethoxy) phenyl) piperazine (intermediate of A173)
1- (3, 4-difluoro-2-methoxyphenyl) piperazine (intermediate of A174)
1- (3-fluoro-2-methoxyphenyl) piperazine (intermediate of A175)
1- (5-fluoro-2-methoxyphenyl) piperazine (intermediate of A176)
1- (2-chlorophenyl) piperazine (intermediate of A198)
1- (4-methoxyphenyl) piperazine (intermediate of A199)
1- (3-methoxyphenyl) piperazine (intermediate of A201)
1- (3-fluoro-4-methoxyphenyl) piperazine (intermediate of A202)
1- (2-chloro-4-fluorophenyl) piperazine (intermediate of A206)
(S) -1- (3-fluoro-5-methoxyphenyl) -2-methylpiperazine (intermediate of A194)
(R) -1- (3-fluoro-5-methoxyphenyl) -2-methylpiperazine (intermediate of A195)
(2S,6R) -1- (3-fluoro-5-methoxyphenyl) -2, 6-dimethylpiperazine (intermediate of A197)
(2R,6R) -1- (3-fluoro-5-methoxyphenyl) -2, 6-dimethylpiperazine (intermediate of A200)
Analytical method
Determination of DOX-induced PD1-ss-Gluc
Flp-In 293T-RExTMpcDNA for cells TM5/FRT/TO plastid transfected with the cDNA encoding Gaussia luciferase inserted fused TO the 3' end of the CDNA encoding the PD1 signal sequence plus 10 amino acids (N-MQIPQAPWPVVWAVLQLGWRPGWFLDSPDR-C) (SEQ ID NO: 1). Selection of transfected cells resistant to the selection markers hygromycin and blasticidin to create cDNA inserts containing PD1-ss +10aa/Gaussia luciferase and capable of being incorporated in T-RExTMA stable cell line in the system that regulates its expression. The day before assay, cells were trypsinized and plated in 384-well tissue culture plates. The following day, compound dilutions in DMSO/broth containing doxycycline were added to the wells and incubated at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Determination of Dox-induced PD1-FL-Gluc
Flp-In 293T-RExTMpcDNA for cells TM5/FRT/TO plastid transfected with a cDNA encoding Firefly Luciferase (Firefly Luciferase) inserted into it fused TO the 3' end of the cDNA encoding the full length of PD1 (amino acids 1-288). Selection of transfected cells resistant to the selection markers hygromycin and blasticidin to create a cDNA insert containing PD 1-FL/firefly luciferase and capable of being transfected at T-RExTMA stable cell line in the system that regulates its expression. The day before assay, cells were trypsinized and plated in 384-well tissue culture plates. The next day, D containing deoxyoxytetracyclineDilutions of compounds in MSO/broth were added to the wells and incubated at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Assay for Dox-induced TNF alpha-FL-Gluc
Flp-In 293T-RExTMpcDNA for cells TM5/FRT/TO plastid transfection with cDNA encoding Gaussia luciferase inserted into the plastid and fused TO the 3' end of the cDNA encoding the full length of TNF α (amino acids 1-233). Selection of transfected cells resistant to the selection markers hygromycin and blasticidin to create a TNF α -FL/Gaussia luciferase cDNA insert that can be incorporated into T-RExTMA stable cell line in the system that regulates its expression. The day before assay, cells were trypsinized and plated in 384-well tissue culture plates. The following day, compound dilutions in DMSO/broth containing doxycycline were added to the wells and incubated at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Determination of Dox-induced IL2-FL-Gluc
Flp-In 293T-RExTMpcDNA for cells TM5/FRT/TO plastid transfection with cDNA encoding Gaussia luciferase inserted into the plastid and fused TO the 3' end of the cDNA encoding the full length of IL-2 (amino acids 1-153). Selection of transfected cells resistant to the selection markers hygromycin and blasticidin to create cells containing IL-2-FL/Gaussia luciferase cDNA insert and can be in T-RExTMA stable cell line in the system that regulates its expression. The day before assay, cells were trypsinized and plated in 384-well tissue culture plates. The following day, compound dilutions in DMSO/broth containing doxycycline were added to the wells and incubated at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Determination of Dox-induced HER3-ss-Gluc
Flp-In 293T-RExTMpcDNA for cells TM5/FRT/TO plastid transfected with cDNA encoding Gaussia luciferase inserted fused TO the 3' end of CDNA encoding HER3 signal sequence plus 4 amino acids (N-MRANDALQVLGLLFSLARGSEVG-C) (SEQ ID NO: 2). Selection of transfected cells resistant to the selection markers hygromycin and blasticidin to create a cDNA insert containing HER3-ss +4aa/Gaussia luciferase and capable of being transfected at T-RExTMA stable cell line in the system that regulates its expression. The day before assay, cells were trypsinized and plated in 384-well tissue culture plates. The following day, compound dilutions in DMSO/broth containing doxycycline were added to the wells and incubated at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
The results for selected compounds provided herein are shown in the table below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Table of HER3 activity
H929 cell viability assay
Culturing human multiple myeloma cell strain NCI-H929 in Advanced RPMI1640 culture solutionThe culture was supplemented with 6% fetal bovine serum, 2mM glutamine and 1 Xpenicillin/streptomycin. On the day of assay, cells were resuspended in RPMI1640 medium supplemented with 10% fetal bovine serum, 2mM glutamine and 1x penicillin/streptomycin and seeded in 384-well tissue culture plates and treated with compound dilutions in DMSO/medium. The plates were incubated at 37 ℃ and 5% CO2The cells were incubated for 48 hours. After 48 hours, will(Promega) were added to each well and luciferase signal was quantified using a Tecan Infinite M1000 Pro to determine cell viability.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
U266 cell viability assay
Human multiple myeloma cell line U266B1 was cultured in RPMI1640 medium supplemented with 10% fetal bovine serum, 2mM glutamine and 1 XPicillin/streptomycin. Cells were seeded in 384-well tissue culture plates and treated with compound dilutions in DMSO/broth. The plates were incubated at 37 ℃ and 5% CO2The cells were incubated for 48 hours. After 48 hours, will(Promega) were added to each well and luciferase signal was quantified using a Tecan Infinite M1000 Pro to determine cell viability.
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Determination of in vitro microsomal stability
Potassium phosphate (423. mu.L in 0.1M solution) was added to 8-line deep well tubes and then human, mouse, rat or monkey microsomes (25. mu.L in 20mg/mL solution) were added. Such deep wells were placed on ice and test subjects (2 μ Ι _ of a 0.25mM solution in DMSO) were added. The mixture was pre-incubated at 37 ℃ for 3 to 5 minutes (shaking at 150 rpm), followed by the addition of 50. mu.L of NADPH to start the reaction. Aliquots of 100 μ L were collected at 0 and 30 minute time points and 200 μ L of an acetonitrile mixture containing IS (Compound 914) was added to quench the reaction. After centrifugation at 4000rpm for 10 minutes, 20. mu.L of the supernatant (20. mu.L) containing the supernatant was injected with 100. mu.LACN/H2Mixed solution of O (1:1) for LC-MS/MS analysis. Liver microsome stability was assessed by the% compound remaining at 30 minutes, which was calculated using the following equation: [ (AUC analyte T ═ 30/AUCIS)/(AUC analyte T ═ 0/AUCIS)]*100。
The results for selected compounds provided herein are shown in table 1 below. For chemical structures that contain one or more stereoisomers without showing stereochemistry, the assay data refers to a mixture of stereoisomers.
Signal sequence-Gluc assay for transient expression of Dox induction
Flp-In 293T-RExTM500ng of pcDNA was used for cells TM5/FRT/TO plastid transfection with cDNA encoding Gaussia luciferase inserted fused TO the 3' end of the cDNA encoding the targeted signal sequence plus 10 amino acids. Transfected cells were cultured overnight, then trypsinized and plated in 384-well tissue culture plates. The following day, compounds in DMSO/broth with doxycycline were dilutedLiquid was added to the wells and at 37 ℃ and 5% CO2And (5) culturing. After 24 hours, coelenterazine substrate was added to each well and luciferase signal was quantified using Tecan Infinite M1000 Pro to determine potency.
Measurement of human Peripheral Blood Mononuclear Cell (PBMC) interleukins
Human PBMCs were freshly isolated from whole blood collections of 3 normal donors using density gradient centrifugation followed by lysis of the red blood cells. PBMCs from each donor were assayed separately. Cells were suspended in RPMI1640 medium supplemented with 5% fetal bovine serum, 2mM glutamine, 10mM HEPES and 1x penicillin/streptomycin. PBMCs were seeded at 200000 cells/well in 96-well round bottom culture plates without stimulation or with lipopolysaccharide (LPS,1 μ g/mL) or antibodies against human CD3 (plate-bound, 2 μ g/mL) and human CD28 (soluble, 2 μ g/mL). Serial dilutions of compounds added simultaneously to DMSO/broth, and PBMC at 37 deg.C, 5% CO2And culturing for 24 hours. After 24 hours, the plates were centrifuged and half of the supernatant volume was removed using an electrochemiluminescence immunoassay (Biomarker Multiplex, Meso Scale Discovery) for cytokine analysis. For survival analysis, will(Promega) was added to the remaining material in each well and quantified via a luminometer reader.
And (3) efficacy research: effect of compound a87 on tumor growth and body weight compared to anti-PD-1 therapy in B16F10 model.
Female C57BL/6 mice (7-8 weeks old) were injected subcutaneously in the flank with 0.1mL of 5X10 on day 06B16F10 cells. On day 3, compound A87 formulated in 10% ETOH/10% Kolliphor EL was administered Intravenously (IV) at 30mg/kg QW, IV 10mg/kg D1D2 or IP 15mg/kg QOD. anti-PD 1 antibody treatment (RMP 1-14,200 μ g obtained from Bioxcell) was administered by abdominal injection (i.p.) with a dose schedule of QODx 3. Tumor size was monitored with a digital caliper (Fowler) every 2-3 days until a size of 1.5-2.0cm was reached and expressed in volume (length X width X height). Melanoma cell line B16F10 was obtained from ATCC. C57/BL6 mice were purchased from Charles Rivers Laboratories.
TABLE 1 Activity of the Compounds
I.a. means IC50 or EC50 is greater than 25 μ M
Claims (78)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
Raand RbEach independently is H or C1-3An alkyl group;
R1is H, OH, C1-3Alkyl, OC1-3Alkyl, ═ CH2Or as NOR5(ii) a Or R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl and forms a spiro ring group with the ring carbon to which it is attached;
R1aand R1bEach independently is H or C1-3An alkyl group;
R2is C1-6Alkyl, N (R)5)2、C3-8Cycloalkyl radical, C3-7Heterocycloalkyl radical, C3-7Heterocycloalkenyl or C6-10An aryl group;
R3is H, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group;
R4is C3-8Cycloalkyl radical, C3-9Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group;
each R5Independently H, C1-3Alkyl or C0-2alkylene-C6-10An aryl group;
x is absent, C1-3Alkylene, C ═ O, or (C ═ O) O;
y is SO or SO2;
Each heterocycloalkyl, heterocycloalkenyl, and heteroaryl independently has 1,2, or 3 ring heteroatoms selected from N, O and S.
2. A compound or salt according to claim 1, wherein each Y is SO.
3. A compound or salt according to claim 1, wherein each Y is SO2。
4. The compound of any one of claims 1-3, wherein RaIs H.
5. The compound of any one of claims 1-3, wherein RaIs C1-3An alkyl group.
6. The compound of claim 5, wherein RaIs CH3。
7. The compound of any one of claims 1-6, wherein RbIs H.
8. The compound of any one of claims 1-6, wherein RbIs C1-3An alkyl group.
9. The compound of claim 8, wherein RaIs CH3。
10. The compound or salt of any one of claims 1-9, wherein R1Is H, OH or NOR5。
11. A compound or salt according to claim 10, wherein R5Is H or CH3。
12. The compound or salt of any one of claims 1-9, wherein R1Is C1-3Alkyl or OC1-3An alkyl group.
13. A compound or salt according to claim 12, wherein R1Is CH3Or OCH3。
14. A compound or salt according to claim 13, wherein R1Is CH3And exhibits S stereochemistry.
15. The compound or salt of any one of claims 1-9, wherein R1Is C3-6Cycloalkyl or C3-6Heterocycloalkyl, and forms a spiro ring group with the ring carbon to which it is attached.
17. The compound or salt of any one of claims 1-9, wherein R1Is ═ CH2。
18. The compound or salt of any one of claims 1-17, wherein R1aAnd R1bEach is H.
19. The compound or salt of any one of claims 1-17, wherein R1aAnd R1bAt least one of them is C1-3An alkyl group.
20. The compound or salt of claim 19, wherein R1aAnd R1bEach is CH3。
21. The compound or salt of any one of claims 1-20, wherein R2Is C1-6Alkyl or N (R)5)2。
22. A compound or salt of claim 21 wherein each R5Independently comprise H, C1-3Alkyl or benzyl.
24. The compound or salt of any one of claims 1-20, wherein R2Comprising C3-8A cycloalkyl group.
25. A compound or salt according to claim 24, wherein R2Including cyclopentyl or cyclohexyl.
26. The compound or salt of any one of claims 1-20, wherein R2Is C3-9Heterocycloalkyl or C3-9A heterocycloalkenyl group.
27. A compound or salt according to claim 26, wherein R2Including oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, or tetrahydropyridinyl.
28. According to claim 26The compound or salt of, wherein C3-7Heterocycloalkyl or C3-7Heterocycloalkenyl groups comprise a bridging group or a spiro group.
30. The compound of claim 29, wherein R6Is optionally substituted by 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy and phenyl substituted by the group of CN.
33. the compound or salt of any one of claims 1-20, wherein R2Is C6-10And (4) an aryl group.
35. The compound or salt of any one of claims 1-34, wherein X is absent.
36. A compound or salt according to claim 35, wherein R3Comprising C1-6Alkyl or H.
37. A compound or salt according to claim 36, wherein R3Is 2-methylbutyl, isopropyl, isoamyl, CH2CH2OCH3、CH2C(CH3)2CN、CH2CF3Or CH2CH2CF3。
38. A compound or salt according to claim 37, wherein R3Is an isobutyl group.
39. The compound or salt of any one of claims 1-34, wherein X is C1-3An alkylene group.
40. A compound or salt according to claim 39, whereinX is CH2、CH2CH2Or CH (CH)3)。
41. A compound or salt according to claim 39 or 40, wherein R3Comprising C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C3-7Heterocycloalkyl radical, C6-10Aryl or C2-6A heteroaryl group.
42. A compound or salt according to claim 41, wherein R3Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl or pyrimidinyl.
46. A compound or salt according to any one of claims 1-34, wherein X is co or (co) O.
47. A compound or salt according to claim 46, wherein R3Comprising C1-6Alkyl or C6-10And (4) an aryl group.
49. The compound or salt of any one of claims 1-48, wherein R4Comprising C3-8Cycloalkyl or C3-9A heterocycloalkyl group.
51. The compound or salt of any one of claims 1-48, wherein R4Comprising C6-10Aryl or C2-9Heteroaryl, and R4Optionally substituted with 1 to 3 substituents independently selected from halogen, C1-3Alkyl radical, C1-3Alkoxy, C (O) N (R)N)2And N (R)N)2Is substituted with a group of (A), and each RNIndependently of each otherIs H or C1-3An alkyl group.
55. The compound or salt of any one of claims 1-54, wherein R1Is (S)) A conformation.
56. A compound, or pharmaceutically acceptable salt thereof, the compound being listed in table a.
58. a compound selected from the group consisting of the compounds listed in table B, or a pharmaceutically acceptable salt thereof.
59. A pharmaceutical composition comprising a compound or salt according to any one of claims 1-58, and a pharmaceutically acceptable carrier.
60. A method of inhibiting protein secretion in a cell comprising contacting the cell with a secretion-inhibiting effective amount of a compound or salt of any one of claims 1-58 or a pharmaceutical composition of claim 59.
61. The method of claim 60, wherein the protein is a checkpoint protein.
62. The method of claim 60, wherein the protein is a cell surface protein, an endoplasmic reticulum-associated protein, or a secreted protein involved in modulating an anti-tumor immune response.
63. The method of claim 60, wherein the protein is at least one of PD-1, PD-L1, TIM-1, LAG-3, CTLA4, BTLA, OX-40, B7H1, B7H4, CD137, CD47, CD96, CD73, CD40, VISTA, TIGIT, LAIR1, CD160, 2B4, TGFR β, and combinations thereof.
64. The method of any one of claims 60-63, wherein said contacting comprises administering said compound or composition to a subject.
65. A method of treating inflammation in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of claims 1-58 or a pharmaceutical composition according to claim 59.
66. A method of treating or preventing cancer or a precancerous condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1-58 or a pharmaceutical composition of claim 59.
67. The method of claim 66, wherein the cancer is melanoma, multiple myeloma, prostate cancer, lung cancer, pancreatic cancer, squamous cell carcinoma, leukemia, lymphoma, neuroendocrine tumor, bladder cancer, or colorectal cancer.
68. The method of claim 66, wherein the cancer is non-small cell lung cancer, squamous cell carcinoma, leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphoma, NPM/ALK-transformed anaplastic large-cell lymphoma, diffuse large B-cell lymphoma, neuroendocrine tumor, breast cancer, mantle cell lymphoma, renal cell carcinoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, small cell carcinoma, adenocarcinoma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, thyroid cancer, anaplastic large-cell lymphoma, hemangioma, or head and neck cancer.
69. The method of claim 66, wherein the cancer is a solid tumor.
70. The method of claim 66, wherein the cancer is head and neck cancer, squamous cell carcinoma, gastric cancer, or pancreatic cancer.
71. A method of treating an autoimmune disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1-58 or the pharmaceutical composition of claim 59.
72. The method of claim 71, wherein the autoimmune disease is psoriasis, dermatitis, systemic scleroderma, sclerosis, Crohn's disease, ulcerative colitis; respiratory distress syndrome, meningitis; encephalitis; uveitis; colitis; glomerulonephritis; eczema, asthma, chronic inflammation; atherosclerosis; white blood cell adhesion defect; rheumatoid arthritis; systemic Lupus Erythematosus (SLE); diabetes mellitus; multiple sclerosis; reynaud's syndrome; autoimmune thyroiditis; allergic encephalomyelitis; sjorgen's syndrome; juvenile onset diabetes; tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia (Addison's disease); diseases involving leukocyte extravasation; central Nervous System (CNS) inflammatory disorders; multiple organ injury syndrome; hemolytic anemia; myasthenia gravis; antigen-antibody complex-mediated diseases; resistance to glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; graves' disease; Lambert-Eaton myasthenia gravis syndrome; bullous pemphigoid; pemphigus; autoimmune polyendocrine gland disease; leiter's disease; stiff-man syndrome (stiff-man syndrome); beheet disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathy; immune Thrombocytopenic Purpura (ITP) or autoimmune thrombocytopenia.
73. A method of treating an immune related disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of claims 1-58 or a pharmaceutical composition according to claim 59.
74. The method of claim 73, wherein the immune related disease is rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, multiple sclerosis, or Crohn's disease.
75. A method of treating a neurodegenerative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of claims 1-58 or a pharmaceutical composition according to claim 59.
76. The method of claim 75, wherein the neurodegenerative disease is multiple sclerosis.
77. A method of treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of claims 1-58 or a pharmaceutical composition according to claim 59.
78. The method of claim 77, wherein the inflammatory disease is bronchitis, conjunctivitis, myocarditis, pancreatitis, chronic cholecystitis, bronchiectasis, aortic valve stenosis, vascular restenosis, psoriasis, or arthritis.
Applications Claiming Priority (5)
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US201862643931P | 2018-03-16 | 2018-03-16 | |
US62/643931 | 2018-03-16 | ||
US201962803704P | 2019-02-11 | 2019-02-11 | |
US62/803704 | 2019-02-11 | ||
PCT/US2019/022533 WO2019178510A1 (en) | 2018-03-16 | 2019-03-15 | Triazacyclododecansulfonamide ("tcd")-based protein secretion inhibitors |
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CN112262129A true CN112262129A (en) | 2021-01-22 |
CN112262129B CN112262129B (en) | 2024-05-14 |
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MA52008A (en) | 2021-04-21 |
IL277252A (en) | 2020-10-29 |
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MX2020009645A (en) | 2020-10-08 |
AU2019236248B2 (en) | 2024-01-18 |
BR112020018767A2 (en) | 2021-01-26 |
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